). Several different types of G proteins exist including inhibitory (G

G

G Protein

Definition

G Proteins are coupling proteins that lead to second- messenger production. They are called G proteins because they bind to guanine-nucleotide proteins. They are located on the cytoplasmic side of the membrane and are activated by the intracellular domain of the receptor protein. The G-protein consists of three func- tional subunits (G

). Several different types of G proteins exist including inhibitory (G

) and stimulatory (G

) proteins. Activation of G

proteins inhibit, and activation of G

proteins stimulate the production of the second messenger adenylate cyclase (cAMP), release of Ca

, activation of enzymes, and changes in gene expression.



Opioids and Inflammatory Pain



Sensitization of Muscular and Articular Nociceptors



Spinothalamic Tract Neurons, Peptidergic Input

G Protein Coupling

Definition

The G

subunit in its resting state is bound to guanine- diphosphate (GDP). After a G protein coupled receptor is activated by its ligand, guanine triphosphate (GTP) is exchanged for guanine diphosphate (GDP), the G

subunit dissociate from the G

subunit, and the G protein dissociates from the OR. Both subunits (G

and G

) can activate down-stream effector systems such as adeny- late cyclase (cAMP), ion channels, and other second- messenger cascades.



Opioids and Inflammatory Pain

G Protein-Coupled Receptor

Synonyms GPCR

Definition

GPCR span the cell membrane seven times, with the amino terminus located extra-cellularly and the carboxy terminus inside the cell. These receptors are coupled to G proteins, which are composed of three units (alpha, beta and gamma), and are located inside the surface of the cell membrane.



Cytokines, Effects on Nociceptors



Opioid Receptor Localization

GABA and Glycine

in Spinal Nociceptive Processing

H

U

Z

Institute for Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

zeilhofer@pharma.unizh.ch Synonyms

Inhibitory Synaptic Transmission Definitions

The spinal cord dorsal horn represents the first site of synaptic integration in nociceptive processing. Here and elsewhere in the spinal cord and brainstem fast inhibitory neurotransmission is mediated by the amino acids

γ-aminobutyricacid (GABA) and glycine. Both transmitters open ligand gated anion channels desig- nated

GABA

receptors and inhibitory (

strychnine -sensitive) glycine receptors, respectively. Their activa- tion impairs transmission of nociceptive signals through the spinal cord to higher brain areas. GABAergic neu- rons and GABA receptors are found throughout the central nervous system, while glycinergic terminals and strychnine-sensitive glycine receptors are largely restricted to in the spinal cord, brainstem and cerebel- lum.

Characteristics Cellular Function

Upon activation, GABA

and strychnine-sensitive

glycine receptors permit the permeation of chloride

(and to a lesser extent of bicarbonate) ions through the

812 GABA and Glycine in Spinal Nociceptive Processing

plasma membrane. This increase in anion conductance inhibits neuronal activity through two major mecha- nisms. First, in most neurons chloride flux is inwardly directed at the physiological resting potential and hy- perpolarizes neurons. Second, activation of dendritic GABA

and glycine receptors causes a “shunting” con- ductance and thereby impairs the dendritic propagation of excitatory postsynaptic currents along the dendrite.

Molecular Structure and Pharmacology

GABA

receptors and strychnine-sensitive glycine receptors are pentameric protein complexes and be- long to the same family as nicotinic acetylcholine and serotonin 5-HT3 receptors. A total of 19 mammalian GABA

receptor subunits are known (α1 – α6, β1 – β3, γ1– γ3, δ, , υ,π, ρ1 – ρ3), each of which is en- coded by a separate gene. The most prevalent form of the GABA

receptor in the CNS is probably α

β2- γ2. GABA

receptors containing α1, α2, α3 or α5 subunits are benzodiazepine sensitive and potentiated by classical benzodiazepines including

diazepam, while α4 and α6 are benzodiazepine-insensitive (for details see Rudolph et al. 2001). The β subunits bind barbiturates and intravenous anesthetics including



propofol and

etomidate, which also facilitate the activation of GABA

receptors.

Bicuculline -insensitive ionotropic GABA receptors have been termed GABA

receptors. They contain ρ subunits, which can in most cases form functional homomeric receptor channels.

GABA

Receptors

In addition to ionotropic GABA

receptors, GABA binds to G-protein coupled GABA

receptors, which are heterodimeric receptors with 7 transmembrane domains. They couple to pertussis toxin-sensitive (in- hibitory) G-proteins, activate G-protein coupled K

channels, inhibit Ca

channels and reduce the forma- tion of c-AMP.

Glycine Receptors

Glycine receptors (GlyRs) show much less diversity than GABA

receptors. Four α subunits, α1 through α4, are known and one β subunit, each encoded by a separate gene. The α subunits bind glycine and are ca- pable of forming functional homomeric or heteromeric ion channels, while the β subunit confers postsynaptic clustering through an interaction with the intracel- lular protein gephyrin. Heteropentameric channels composed of GlyR α1 and GlyRβ subunits constitute the most prevalent adult strychnine-sensitive glycine receptor isoform (for details see Legendre 2001).

Glycine serves a dual role in spinal neurotransmission.

It not only binds to inhibitory glycine receptors but also to a strychnine-insensitive binding site at excita- tory glutamate receptors of the N-methyl D-aspartate (

NMDA) subtype. These receptors are primarily gated by glutamate, but require glycine as an obligatory

coagonist. Increasing evidence meanwhile indicates that glycine binding to NMDA receptors is not satu- rated under resting conditions; opening the possibility that NMDA receptor activity is modulated by changes in extracellular glycine. A recent study suggests that



spillover of glycine synaptically released from in- hibitory interneurons contributes to the facilitation of NMDA receptor activation in the spinal cord dorsal horn to facilitate nociception (Ahmadi et al. 2003).

Synthesis, Storage and Re-uptake of GABA and Glycine GABA is synthesized through two isoforms of

glu- tamic acid decarboxylase (GAD-65 and GAD-67). In the ventral horn, GAD-67 is predominant, while both forms coexist in the dorsal horn. Unlike GABA, glycine is a proteogenic amino acid and therefore ubiquitously present. In glycinergic neurons it accumulates, probably through specific uptake from the extracellular space.

Following synaptic release, glycine and GABA are removed from the synaptic cleft and taken up by spe- cific membrane associated transporters, which belong to the family of Na

-Cl

-dependent neurotransmit- ter transporters. Two forms of

glycine transporters (

GlyT-1 and

GlyT-2) exist. GlyT-2 is primarily expressed in glycinergic neurons and hence restricted mainly to the spinal cord, brainstem and cerebellum.

GlyT1 is mainly found on astrocytes and expressed more widely in the CNS. GlyT1 is believed to me- diate fast removal of glycine from the synaptic cleft, whereas GlyT2 mediates the recycling of glycine in glycinergic neurons. A role for both transporters in spinal nociceptive processing has been proposed, but is not yet firmly established. Five types of

GABA transporters (GAT1, GAT2, GAT3, BGT1, TAUT) have been identified. Their contribution to spinal nociceptive processing is also unclear. The transport of GABA and glycine into the presynaptic storage vesicles is mediated by the

vesicular inhibitory amino acid transporter (VIAAT).

GABA and Glycine in the Dorsal Horn

Blockade of spinal GABA

(with e.g.

bicuculline) and GABA

receptors (with e.g. phaclofen) produces tactile allodynia and thermal hyperalgesia, while ion- tophoretic application of GABA diminishes the size of cutaneous receptive fields of dorsal horn projection neurons. At the spinal cord level, benzodiazepines inhibit the propagation of nociceptive input through the spinal cord. Although antinociceptive effects of benzodiazepines have been reported in animal models, particularly after intrathecal injection, their systemic unse does not induce apparent analgesia in humans.

This may be due to a potentiation of GABA receptors

in supraspinal CNS areas, where GABA inhibits de-

scending antinociceptive neurons and hence increases

pain. The subunit composition of GABA

receptors

exhibits characteristic differences through the different

G

GABA and Glycine in Spinal Nociceptive Processing 813

laminae of the spinal cord. In laminae I and II α2 and α3 are abundant, while α1 and α5 are almost absent.

Deeper dorsal horn laminae show less specific subunit expression (Bohlhalter et al. 1996). The contribution of the different GABA

receptor subunits to the spinal control of nociception has not yet been systematically evaluated.

Compared with GABA, the contribution of endoge- nous glycine to nociception is more difficult to assess because of its prominent role in the control of motor function. However, spinal application of strychnine in rats, experiments with glycine receptor-mutant mice (spastic mice) and accidental poisoning of humans with strychnine indicate an important role of glycine in the spinal control of nociception. Within the dorsal horn, glycinergic dendrites and somata are postsynaptic to myelinated primary afferent terminals suggesting that glycine may be primarily involved in the processing of input from low threshold mechanoreceptors. However, glycinergic neurons have also been reported to be post- synaptic to substance P containing terminals indicating that they also receive input from C fiber nociceptors.

Like GABA

receptors, glycine receptors exhibit a characteristic pattern of expression in the spinal cord dorsal horn. While the GlyRα1 and GlyR β subunits are rather homogeneously distributed throughout the different laminae, GlyRα3 shows a distinct expression in the superficial dorsal horn, where thinly myelinated and unmyelinated primary afferents terminate (Fig.

1). Glycinergic neurotransmission in this CNS area is inhibited by nanomolar concentrations of PGE

through protein kinase A-dependent phosphorylation (Ahmadi et al. 2002). Mice deficient in the GlyRα3 subunit not only lack PGE

-mediated inhibition of glycine receptors, but also show a dramatic reduction in central inflammatory pain sensitization, identifying PGE

-mediated inhibition of glycinergic neurotrans- mission as the dominant mechanism of inflammatory hyperalgesia (Harvey et al. 2004). The prevention of this process probably constitutes the major analgesic mechanism of action of cyclooxygenases inhibitors (Fig. 2).

These and other recently reported findings indicate that a

disinhibition of spinal nociceptive neurons through a decrease in inhibitory dorsal horn neurotransmission plays a key role in the development of chronic patholog- ical pain states, including chronic

neuropathic pain.

Peripheral nerve injury causes a transsynaptic decrease in the expression of a potassium chloride transporter (KCC2), which reduces the chloride gradient of lamina I dorsal horn neurons and in turn reduces the inhibitory effect of GABAergic and glycinergic input (Coull et al.

2003). Furthermore, it has recently been proposed that neuropathic pain is associated with

apoptotic degen- eration of inhibitory mainly GABAergic interneurons in the spinal cord (Moore et al. 2002), but the data is still controversial (Polgar et al. 2003).

GABA and Glycine in Spinal Nociceptive Processing, Figure 1 Theα3 subunit of strychnine-sensitive glycine receptors (GlyRα3) exhibits a dis- tinct expression pattern in the spinal cord dorsal horn. (a) GlyRα3 staining (green) is almost exclusively found in the superficial laminae of the spinal cord dorsal horn, where nociceptive afferents terminate, while gephyrin, a postsynaptic protein which anchors glycine and GABA receptors in the post- synaptic membrane, is ubiquitously distributed throughout the gray matter of the spinal cord. (b) Co-staining of GlyRα3 (blue) with calcitonin gene related peptide (CGRP, green), a marker of peptidergic primary afferent nerve fibers, and GlyRα1 (red), the most abundant adult glycine recep- tor subunit. (Modified from Harvey et al. GlyRα3: an essential target for spinal PGE₂-mediated inflammatory pain sensitization. Science 304:884- 887, 2004).

GABA

Receptors on Primary Afferent Neurons

Primary sensory neurons achieve an unusually high

intracellular chloride concentration due to the expres-

sion of a

Na

K

Cl

cotransporter (slc12a2), which

accumulates Cl

inside cells, and the lack of K

Cl-

cotransporters, which extrude Cl

from cells, (Kanaka

et al. 2001). This peculiar expression pattern causes

GABAergic input to depolarize central terminals of

these neurons and causes GABA

receptor-mediated

primary afferent depolarization (PDA). This depolar-

ization can lead to voltage-dependent inactivation of

ion channels in the terminal and thereby reduce trans-

814 GABA Mechanisms and Descending Inhibitory Mechanisms

GABA and Glycine in Spinal Nociceptive Processing, Figure 2 Schematic diagram illustrating the pathway leading to PGE₂-mediated reduction of inhibitory glycinergic neurotransmission in the superficial layers of the spinal cord dorsal horn. PGE₂binds to postsynaptic EP2 receptors, which activate adenylyl cyclase and finally trigger protein kinase A-dependent phosphorylation and inhibition of GlyRα3.

mitter release (

presynaptic inhibition). Under certain conditions, primary afferent depolarization may be- come supra-threshold and then evoke retrograde action potentials giving rise to so-called

dorsal root reflexes.

Therapeutic Interventions Targeting Spinal GABA and Glycine Receptors

Although the role of glycine and GABA in spinal noci- ceptive processing is increasingly recognized, only very few analgesic drugs target these transmitter systems so far. Systemic and intrathecal

baclofen, an agonist at GABA

receptors, has been successfully used in pain patients suffering from multiple sclerosis or after spinal cord injury. Antagonists at the glycine-binding site of NMDA receptors are currently being developed for the treatment of chronic pain states. Blockade of the glycine- binding site of NMDA receptors has proven antinocicep- tive in several animal models of pain including chronic neuropathic pain.

References

1. Ahmadi S, Lippross S, Neuhuber WL et al. (2002) PGE₂se- lectively blocks inhibitory glycinergic neurotransmission on rat superficial dorsal horn neurons. Nat Neurosci 5:34–40 2. Ahmadi S, Muth-Selbach U, Lauterbach A et al. (2003) Facilita-

tion of spinal NMDA receptor-currents by synaptically released glycine. Science 300:2094–2097

3. Bohlhalter S, Weinmann O, Möhler H et al. (1996) Laminar compartmentalization of GABA_A-receptor subtypes in the spinal cord: an immunohistochemical study. J Neurosci 16:283–297

4. Coull JA, Boudreau D, Bachand K et al. (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942

5. Harvey RJ, Depner UB, Wässle H et al. (2004): GlyRα3: An es- sential target for spinal inflammatory pain sensitization. Science 304:884–887

6. Kanaka C, Ohno K, Okabe A et al. (2001) The differential expres- sion patterns of messenger RNAs encoding K-Cl cotransporters (KCC1,2) and Na-K-2Cl cotransporter (NKCC1) in the rat ner- vous system. Neuroscience 104:933–946

7. Legendre P (2001) The glycinergic inhibitory synapse. Cell Mol Life Sci 58:760–793

8. Moore KA, Kohno T, Karchewski LA et al. (2002) Partial periph- eral nerve injury promotes a selective loss of GABAergic inhibi- tion in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731

9. Polgar E, Hughes DI, Riddell JS et al. (2003) Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 104:229–239 10. Rudolph U, Crestani F, Möhler H (2001) GABA_Areceptor sub-

types: dissecting their pharmacological functions. Trends Phar- macol Sci. 22:188–194

GABA Mechanisms and Descending Inhibitory Mechanisms

W

D. W

Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA

wdwillis@utmb.edu Synonyms

Centrifugal Control of Nociceptive Processing; Supra- spinal Regulation; endogenous analgesia system;

GABAergic Inhibition; Descending Inhibitory Mecha- nisms and GABA Mechanisms

Definition

Pathways that originate in the brain can inhibit nocicep- tive neurons in the dorsal horn, including spinothalamic tract (STT) cells. Several different inhibitory neuro- transmitters are used by the endogenous analgesia system. One of these is gamma-aminobutyric acid (GABA). GABA can be released either directly by the axons of brainstem neurons that descend to the spinal cord or indirectly by the excitation of GABAergic in- hibitory interneurons in the spinal cord through release of excitatory transmitters from descending axons. There are several mechanisms for GABAergic inhibitory ac- tions. These include pre- and post-synaptic inhibition following actions of GABA on GABA

or GABA

receptors.

Characteristics



Gamma( γ)-Aminobutyric Acid (GABA) is a major inhibitory neurotransmitter in the spinal cord, espe- cially in the dorsal horn (Willis and Coggeshall 2004).

Its synthetic enzyme is

glutamic acid decarboxylase

G

GABA Mechanisms and Descending Inhibitory Mechanisms 815

(GAD). There are several forms of GAD. The sources of GABAergic terminals in the spinal cord include GABAergic spinal interneurons (see

GABAergic Cells (Inhibitory Interneurones)) (Carlton and Hayes 1990) and axons that descend from the rostral ventral medulla (Millhorn et al. 1987; Reichling and Bas- baum 1990). GABA-containing synapses have been demonstrated on primate spinothalamic tract cells in an electron microscopic study (Carlton et al. 1992). GABA is also contained in presynaptic contacts with primary afferent terminals (Willis and Coggeshall 2004).

There are at least 3 types of GABA receptors (see



GABAA Receptors and GABAB Receptors), GABA

, GABA

and GABA

receptors. Emphasis here will be on the first two of these. GABA

receptors are iontotropic receptors and cause the opening of chlo- ride channels (Willis and Coggeshall 2004). This can result in either a hyperpolarization or a depolarization, depending on where Cl

is concentrated. The concen- tration of Cl

depends on the type of

Cl

Transporter that is present in the neuronal membranes (Willis and Coggeshall 2004; Willis 1999). In the case of presy- naptic endings, GABA

receptor activation results in primary afferent depolarization and

presynaptic inhibition (Willis 1999). In the case of postsynaptic neurons, GABA

receptors cause hyperpolarization and

postsynaptic inhibition (Willis and Coggeshall 2004).

GABA

receptors are metabotropic G-protein coupled receptors (see

Metabotropic Glutamate Receptors) (Willis and Coggeshall 2004). They are found both pre- and post-synaptically. Their activation can also cause pre- or post-synaptic inhibition. However, presynaptic inhibition in this case is not accompanied by primary afferent depolarization. Instead, it is due to a reduc- tion in the Ca

current that is necessary for release of transmitter from presynaptic terminals. Postsynaptic inhibition that is mediated by GABA

receptors results from an increased conductance for K

ions.

Experiments in which drugs were released by

micro- iontophoresis near primate STT cells have shown that the excitation of these neurons by the pulsed release of glutamate or by noxious compression of the skin can be reduced by GABA (Fig. 1) (Willcockson et al. 1984).

The iontophoretic release of the GABA

receptor ag- onist, muscimol, also inhibited the activity of all of the STT cells tested (Lin et al. 1996a). However, the GABA

receptor agonist, baclofen, produced inhibition in only 17% of STT cells examined. On the other hand, micro- dialysis administration of baclofen into the dorsal horn resulted in a strong inhibition of STT cells (Fig. 2). This was counteracted by co-administration of the GABA

receptor antagonist, phaclofen.

Microdialysis admin- istration of the GABA

antagonist, bicuculline or the GABA

receptor antagonist, phaclofen enhanced the re- sponses of STT cells (Lin et al. 1996a). This evidence suggests that GABA

receptors are likely to be more im-

GABA Mechanisms and Descending Inhibitory Mechanisms, Figure 1 Inhibition of the activity of a primate spinothalamic tract (STT) neuron by iontophoretic release of GABA. (a) shows the responses of an STT cell to pulsed release of glutamate. The iontophoretic currents lasted for 5 s and were repeated at 10 s intervals. At the times indicated by the horizontal bars, GABA was also released, using the indicated currents.

(b) shows the inhibitory effects of GABA release on the responses of the same STT neuron to continuous noxious pinch of the skin in the receptive field. The iontophoretic currents are indicated. (From (Willcockson et al.

1984).)

portant for presynaptic inhibition than for postsynaptic inhibition.

Stimulation in the midbrain

periaqueductal gray

(PAG) can produce a strong inhibition of the responses

of nociceptive dorsal horn neurons, including STT cells

(Hayes et al. 1979). This inhibition is at least partly

due to the effects of the release of GABA in the spinal

cord (Lin et al. 1996a; Peng et al. 1996). Evidence for

this was obtained by administration of antagonists of

GABA receptors into the spinal cord by microdialy-

sis. The antagonists reduced the amount of inhibition

produced by PAG stimulation. GABA

receptors are

activated by PAG stimulation, since PAG inhibition

is partially blocked by the GABA

antagonist, bicu-

culline (Fig. 3). GABA

receptors are less involved in

PAG inhibition of STT cells, since administration of

the GABA

antagonist, phaclofen reduced the inhibi-

tion produced by PAG stimulation in only 22% of the

816 GABA Mechanisms and Descending Inhibitory Mechanisms

GABA Mechanisms and De- scending Inhibitory Mechanisms, Figure 2 Inhibition of the activity of a primate STT cell by spinal cord microdialysis administration of baclofen and the antagonistic effect of phaclofen.

(a) left histogram, shows the background discharge of an STT cell. During the time indicated by the horizontal bar, baclofen was infused into the spinal cord by microdialysis. (a) right histogram, shows the antagonistic action of phaclofen when this agent was co-administered with baclofen. (b) shows the inhibitory effects of baclofen on the responses of the neuron to brush and pinch stimuli and to noxious heat. The stimuli were applied at the times indicated by the horizontal bars or by the temperature monitor. The upper row of histograms shows the control responses, the middle row the inhibited responses during baclofen administration and the lower row the responses when phaclofen was co-administered with baclofen. In (c), baclofen is shown to block orthodromic but not antidromic responses of the STT cell. The effect was reversed by phaclofen. (From Lin et al.

1996a).

STT cells tested. Thus, GABA, as well as opioids and monoamines, such as serotonin and norepinephrine is one of the inhibitory neurotransmitters utilized by the



endogenous analgesia system (Willis and Coggeshall 2004).

The inhibitory action of GABA has been shown to have an important antinociceptive action (see



Antinoception) in the spinal cord that is mediated by GABA

receptors (Aanonsen and Wilcox 1989).

Release of GABA has been offered as an explanation for the antinociceptive effects of spinal cord stimula- tion (Linderoth et al. 1994). In contrast, antagonism of GABA

receptors in rats produces a profound state of



mechanical allodynia (Sivilotti et al. 1994). Consis- tent with this is the observation that the inhibition of primate STT cells produced by iontophoretic applica- tion of GABA or muscimol is greatly reduced during the

central sensitization that follows intradermal injection of capsaicin (Lin et al. 1996b). Central sen- sitization is likely to be due to both an increase in the responsiveness of excitatory amino acid receptors and to a decrease in the responsiveness of inhibitory amino acid receptors (Willis and Coggeshall 2004).

References

1. Aanonsen LM, Wilcox GL (1989) Muscimol,γ-aminobutyric acid_Areceptors and excitatory amino acids in the mouse spinal cord. JPET 248:1034–1038

2. Carlton SM, Hayes ES (1990) Light microscopic and ultrastruc- tural analysis of GABA-immunoreactive profiles in the monkey spinal cord. J Comp Neurol 300:162–182

3. Carlton SM, Westlund KN, Zhang D et al. (1992) GABA- immunoreactive terminals synapse on primate spinothalamic tract cells. J Comp Neurol 322:528–537

4. Hayes RL, Price DD, Ruda MA et al. (1979) Suppression of no- ciceptive responses in the primate by electrical stimulation of the brain or morphine administration: behavioral and electrophysi- ological comparisons. Brain Res 167:417–421

5. Lin Q, Peng YB, Willis WD (1996a) Role of GABA receptor subtypes in inhibition of primate spinothalamic tract neurons:

difference between spinal and periaqueductal gray inhibition. J Neurophysiol 75:109–123

6. Lin Q, Peng YB, Willis WD (1996b) Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is re- duced during central sensitization. J Neurophysiol 76:1005–1014 7. Linderoth B, Stiller CO, Gunasekera L et al. (1994) Gamma- aminobutyric acid is released in the dorsal horn by electrical spinal cord stimulation: an in vivo microdilalysis study in the rat. Neurosurgery 34:484–488

8. Millhorn DE, Hökfelt T, Seroogy K et al. (1987) Immunohisto- chemical evidence for colocalization ofγ-aminobutyric acid and serotonin in neurons of the ventral medulla oblongata projecting to the spinal cord. Brain Res 410:179–185

9. Peng YB, Lin Q, Willis WD (1996) Effects of GABA and glycine receptor antagonists on the activity and PAG-induced inhibition of rat dorsal horn neurons. Brain Res 736:189–201

10. Reichling DB, Basbaum AI (1990) Contribution of brainstem GABAergic circuitry to descending antinociceptive control.

I. GABA-immunoreactive projection neurons in the peri- aqueductal gray and nucleus raphe magnus. J Comp Neurol 302:370–377

11. Sivilotti L, Woolf CJ (1994) The contribution of GABAAand glycine receptors to central sensitization: disinhibition and touch- evoked allodynia in the spinal cord. J Neurophysiol 782:169–179

G

GABA_BReceptors 817

GABA Mechanisms and Descending Inhibitory Mecha- nisms, Figure 3 Reduction in the PAG inhibition of nociceptive dorsal horn neurons in the rat spinal cord following microdialysis administration of the GABA_A receptor antagonist, bicuculline.

The upper row of histograms in (a) show repeated periods of inhibition of the responses of a dorsal horn neuron to brush, press and pinch stimuli due to four periods of stimulation in the periaqueductal gray (PAG). The stimulus monitor pulses in the lowest row of records indicate the timing of PAG stimulation.

The second row of histograms shows that the PAG inhibition was blocked during the microdialysis administration of bicuculline into the spinal cord. The third row of histograms shows recovery from the bicuculline. (b) shows the grouped results for 19 dorsal horn neurons. Bicuculline infusion resulted in a significant reduction in the PAG inhibition. (From Peng et al. 1996).

12. Willcockson WS, Chung JM, Hori Y et al. (1984) Effects of iontophoretically released amino acids and amines on primate spinothalamic tract cells. J Neurosci 4:732–740

13. Willis WD (1999) Dorsal root potentials and dorsal root reflexes:

a double-edged sword. Exp Brain Res 124:395–421

14. Willis WD, Coggeshall RE (2004) Sensory Mechanisms of the Spinal Cord, 3rd edn. Kluwer Academic/Plenum Publishers, New York

GABA Transporter

Definition

Plasma membrane transporters, which transport GABA into neurons and glial cells.



GABA and Glycine in Spinal Nociceptive Processing

GABA _A Receptors

Definition

An Ionotropic (bicuculline-sensitive) γ-amino butyric acid (GABA) receptor. GABA

receptors are ionotropic (gating primarily Cl

and K

currents) and typically me- diate fast inhibitory processes.



GABA and Glycine in Spinal Nociceptive Processing

GABA _B Receptors

Definition

GABA

is a type of receptor for the inhibitory amino acid γ-amino butyric acid. GABA

receptors are metabotropic and typically mediate slower inhibitory processes.



GABA Mechanisms and Descending Inhibitory Mechanisms



Nociceptive Neurotransmission in the Thalamus



Thalamic Plasticity and Chronic Pain

818 GABAergic

GABAergic

Definition

Synaptic transmission at which the γ-amino acid GABA (γ-aminobutyric acid) is used as an inhibitory neuro- transmitter.



Opioid Receptors at Postsynaptic Sites

GABAergic Cells (Inhibitory Interneurones)

Definition

GABAergic cells are neurons that use gamma-amino- butyric acid (GABA), an inhibitory neurotransmitter, as their neurotransmitter. GABAergic inhibitory in- terneurones are local circuit inhibitory neurones that use GABA as their neurotransmitter.



GABA Mechanisms and Descending Inhibitory Mechanisms



Nociceptive Neurotransmission in the Thalamus



Thalamic Nuclei Involved in Pain, Cat and Rat



Thalamocortical Loops and Information Processing

GABAergic Inhibition



GABA Mechanisms and Descending Inhibitory Mechanisms

Gabapentin

Definition

Gabapentin is an antiepileptic drug that is also effective in neuropathic pain conditions as, for example, posther- petic neuralgia and diabetic neuropathy. It is very likely that gabapentin may reduce phantom pain.



Migraine, Preventive Therapy



Postoperative Pain, Gabapentin



Postoperative Pain, Postamputation Pain, Treatment and Prevention

GAD



Glutamic Acid Decarboxylase

Gainful Work Activity

Definition

Gainful work activity is that which is done for pay or profit. Work activity is gainful if it is the kind of work usually done for pay or profit whether or not a profit is realized.



Disability Evaluation in the Social Security Admin- istration

Galactorrhea

Definition

Galactorrhea is the normal production and flow of milk after pregnancy. This condition is considered abnormal in the absence of recent pregnancy.



Cancer Pain Management, Opioid Side Effects, En- docrine Changes and Sexual Dysfunction

Galanin

Definition

Galanin is a 29–amino acid peptide (30 in humans), which was purified from porcine intestine. It is widely distributed in the nervous system and has inhibitory effects on its target cells. Galanin-containing dorsal root ganglion neurons seem to play a role in pain pro- cessing, particularly following nerve injury. Roles in the central control of feeding, body weight and affect are also discussed.



Neuropeptide Release in the Skin

Gamma Knife

Definition

A gamma knife is a highly specific and focused, non- invasive, gamma radiation device used as a surgical unit.



Cancer Pain Management, Anesthesiologic Interven- tions

Gamma( γ)-Aminobutyric Acid

Synonym

GABA

G

Ganglionopathies 819

Definition

GABA is a biologically active amino acid found in plants as well as in the brain and other animal tissues. One of the principle inhibitory amino acid neurotransmitters in the central nervous system. GABA acts as an agonist at two receptors, the GABA

receptor, which is a chloride channel, and the GABA

receptor, which is a G-protein linked receptor. Primary afferent depolarization in the central nervous system is thought to be mediated by the release of GABA at axo-axonic synapses. Activation of GABA

receptors by synaptically released GABA de- polarizes the central terminals of afferent fibers, increas- ing their excitability. It is found primarily in inhibitory interneuros throughout the neuraxis.



GABA Mechanisms and Descending Inhibitory Mechanisms



GABA and Glycine in Spinal Nociceptive Processing



Molecular Contributions to the Mechanism of Central Pain



Nociceptors in the Orofacial Region (Temporo- mandibular Joint and Masseter Muscle)



Somatic Pain



Spinal Cord Nociception, Neurotrophins



Stimulation-Produced Analgesia



Thalamic Neurotransmitters and Neuromodulators



Thalamic Plasticity and Chronic Pain

Ganglionopathies

J

W. G

Department of Neurology Johns Hopkins University School of Medicine, Departments of Neuroscience and Pathology Johns Hopkins Hospital, Baltimore, MA, USA

jgriffi@jhmi.edu Synonyms

Sensory Neuronopathy; Sensory Ganglionitis; Idio- pathic Ataxic Neuropathy

Definition

A group of disorders of the peripheral nervous system characterized by loss of primary sensory neurons in the dorsal root ganglia, with or without concomitant loss of autonomic neurons from the peripheral ganglia.

Characteristics

The primary sensory neurons lie in the dorsal root ganglia and cranial nerve ganglia. In a group of dis- orders of the peripheral nervous system (PNS) they degenerate and are lost, along with their peripheral and central axons. There are several etiologies that can produce such sensory ganglionopathies, includ-

ing inflammatory, toxic, and infectious causes. Most types of sensory ganglionopathies affect large sensory neurons and so produce loss of proprioception, joint po- sition sensibility, and kinesthesia (Denny-Brown 1948;

Griffin et al. 1990; Kuntzer et al. 2004; Windebank et al. 1990).When the legs are affected there is sensory ataxia, characterized by ataxia associated with the in- ability to stand with they eyes closed (Romberg’s sign).

When the arms are affected there is typically drift of the outstretched arms with the eyes closed, associated with “piano-playing” involuntary movements in the fingers (pseudoathetosis). Pseudoathetosis is easiest to see with the arms outstretched, but in severe cases it can be recognized in the hands at rest. A useful test is to ask the patient to find the thumb of one hand with the index finger of the other without visual guidance. In normal individuals this is a prompt, secure movement.

In patients with loss of kinesthesia, the moving hand must search for the thumb. In the most severe cases, so much touch sensibility is lost, that the patient may not recognize when contact is made.

These features reflect loss of sensation from relatively proximal levels of the arms and legs. Most nerve diseases produce length-dependent loss of function, so that sen- sation is lost in the toes and feet first, and only with ad- vanced disease would gait ataxia, drift of the arms, and pseudoathetosis develop. Thus a characteristic feature of the ganglionopathies is the loss of large-fiber sensory functions, which is not length-dependent in fashion, so that short as well as long nerves are affected.

Spontaneous sensations (tingling paresthesias or burn- ing pain) may be present in affected regions. Reflecting the nonlength-dependent pathology, the affected re- gions frequently include the face and the trunk (Denny- Brown 1948; Griffin et al. 1990; Windebank et al. 1990), regions rarely affected in length-dependent axonal de- generations. A characteristic electrodiagnostic finding is loss of sensory nerve action potential (SNAP) am- plitudes in a nonlength-dependent fashion – the SNAP amplitudes from the ulnar, median, or radial nerves may be reduced at times when the responses from the sural nerves in the legs are still elicitable, or all SNAP responses may be lost at the same time (Lauria et al. 2003). In length-dependent axonal degenerations the sural SNAP amplitude is reduced or lost well before the SNAP amplitudes in the arms. There are two other indications that the neuronal loss in ganglionopathies is nonlength-dependent. First, magnetic resonance imaging (MRI) of the spinal cord shows evidence of fiber loss in the dorsal column at all levels of the spinal cord, reflecting loss of the central processes of large primary afferent neurons (Lauria et al. 2000). In length- dependent axonal degenerations, loss of fibers in the dorsal columns occurs first in the rostral gracile tract.

Second, skin biopsies immunostained for nerve fibers

show loss of nerve fibers from proximal sites such as

the thigh, back, and chest, as well as distal sites (Lauria

820 Ganglionopathies

et al. 2001). In length-dependent axonal degeneration fibers are lost first from the distal leg.

Immune-Mediated Ganglionopathies

Three disorders are included under the designation sen- sory ganglionitis: carcinomatous sensory neuropathy, ataxic neuropathy associated with Sjogren’s syndrome, and idiopathic sensory neuronopathy. All share the pathologic features of lymphocytic infiltration of dorsal root ganglia and destruction of sensory neurons. As indicated in Table I, there are clinical differences that allow suspicion of the correct diagnosis in the clinic.

Carcinomatous Sensory Neuropathy

This disorder was the first recognized sensory gan- glionopathy (Denny-Brown 1948), and its diagnosis has special urgency because it may be the presenting manifestation of an underlying malignancy. Sensory ganglionopathy can be associated with underlying lung, breast, ovary, or other carcinomas. The pathology is an intense lymphocytic infiltration of the dorsal root ganglia, often with autoaggressive T cells invading the sensory nerve cells (Denny-Brown 1948). The initial symptom is often neuropathic pain that involves the hands, trunk, and/or face as well as the feet. The sen- sory loss is global, as reflected in nerve biopsies that show loss of small myelinated and unmyelinated fibers as well as large myelinated fibers. Some individuals have evidence of CNS involvement such as dementia, cerebellar dysfunction, or myelopathy. The spinal fluid often has a mild lymphocytic pleocytosis and elevated protein. A key diagnostic test is a search for antineuronal antibodies associated with sensory ganglionopathies.

These antibodies include anti-Hu antibodies, also called ANNA-1 antibodies, directed against a 37 kD nuclear antigen. Other antibodies include anti-ampiphysin an- tibodies, ANNA-2, and ANNA-3. Patients who present with subacute sensory ganglionopathy require meticu- lous examination for underlying carcinoma, especially when one of these antibodies is detected.

Ganglionopathies, Table 1 Sensory Ganglionitis Syndromes

Feature Sicca syndrome Idiopathic Carcinomatous

Female predilection Marked Modest Absent

Course Variable, acute to chronic Variable, acute to chronic Subacute

Progression Variable, may stabilize or improve Variable, may stabilize or improve Progressive Fiber predilection Large fiber, kinesthetic loss Large fiber, kinesthetic loss More global Associated central nervous system

involvement

Usually none None Cerebellar involvement

Serologic studies ANA⁺, elevated IgG Normal Anti-Hu in many

Antineuronal nuclear antibody - - +

Cerebrospinal fluid Normal Normal Some cells, protein

Nerve biopsy Inflammation, large fiber loss Large fiber loss More global fiber loss

The course is usually inexorable, although occasionally the disease stabilizes. Early discovery of the neoplasm can be life-saving, and occasionally results in stabiliza- tion of the ganglionopathy. Immunosuppressive thera- pies have had disappointing results. Control of the neu- ropathic pain is often difficult and may require opiates.

Ataxic Ganglionopathy with Features of Sjogren’s Syndrome

Sjogren’s syndrome is an autoimmune rheumatologic disorder that includes dry eyes, dry mouth, and serologic abnormalities that often include anti-nuclear antibod- ies. The dry mouth and dry eyes reflect lymphocytic infiltration of the salivary and lacrimal glands, respec- tively. Testing for tear production (Shirmer test) and lip biopsy (minor salivary gland biopsy), and looking for lymphocytic inflammation are adjuncts to the diag- nosis. Several types of neuropathy can be associated with Sjogren’s syndrome (Griffin et al. 1990; Mell- gren et al. 1989). In typical Sjogren’s syndrome, it has been shown that ataxic neuropathy is rare, whereas multiple mononeuropathies and axonal sensorimotor neuropathies are frequently encountered. In the gan- glionopathy, the ocular and other features of Sjogren’s syndrome are often minor, and the neuropathy is usually the presenting manifestation (Griffin et al. 1990). The ataxic neuropathy patients thus form a distinct subgroup of the Sjogren’s patients.

Ataxic neuropathy associated with features of Sjogren’s syndrome is a syndrome that can be recognized by clini- cal and laboratory testing. The laboratory features useful in recognizing this syndrome are positive Schirmer and rose bengal tests for dry eyes and keratitis respectively, inflammation of the minor salivary glands on lip biopsy, and a markedly abnormal antinuclear antibody titer, with or without the Ro or La reactivity often associated with Sjogren’s syndrome.

The neurologic examination is similar to the other gan-

glionopathies, with sensory ataxia and loss of kines-

G

Ganglionopathies 821

thesia in the arms (Griffin et al. 1990). Autonomic dysfunction, reflected in orthostatic hypotension and loss of heart period variability, is common. A character- istic abnormality is the development of Adie’s pupils, unilaterally or bilaterally (Griffin et al. 1990). Adie’s pupils are mid-position pupils with a slow reaction to changes in illumination, prompt reconstriction to accommodation, and vermicular movements under a slit lamp. Bilateral Adie’s pupils are sufficiently rare in other disorders that they suggest the possibility of Sjogren’s ganglionopathy.

The histologic appearance is remarkable for a variable degree of neuronal loss and marked lymphocytic infiltra- tion of the ganglia and dorsal roots (Griffin et al. 1990).

In cutaneous sensory nerves,large myelinated fibers are lost. Small myelinated and unmyelinated fiber densities are relatively preserved. Several nerve biopsy specimens have had small perivascular inflammatory cuffs around epineurial vessels.

In general, attempts at immunotherapy have proved dis- appointing. In most patients, oral and intravenous cor- ticosteroids, cyclophosphamide, and azathioprine have had no obvious effect on the course of the disorder, al- though a slowing of the progression cannot be excluded.

Most patients received their initial therapy at a time when SNAPs were markedly reduced or absent, making the likelihood of recovery low. Rare patients with relatively preserved SNAPs stabilize or improve after treatment with intravenous methylprednisolone and oral azathio- prine.

Idiopathic Sensory Neuronopathy

This category, one of the most frequent causes of sensory ganglionopathy, includes patients with acute, subacute, and chronic disease courses (Windebank et al. 1990). In the acute form, devastating sensory loss develops over a few days. The spinal fluid protein value may be normal or elevated. Results of other laboratory tests are normal and useful principally in excluding Sjogren’s syndrome and occult cancer. Pathologic studies have been rare, but the results have been similar to the findings in Sjogren’s syndrome with sensory ganglionitis.

The prognosis is highly variable, but in time the majority of patients with this disorder are able to return to their previous career (Windebank et al. 1990). The role of ther- apy is uncertain; most patients have received corticos- teroids at some point, and such therapy may minimize progression (Windebank et al. 1990). More important are reassurance, gait training and safety instruction, as described below.

The Fisher Syndrome

The Fisher syndrome is a variant of the Guillain Barre syndrome that is characterized by ataxia, loss of reflexes, and inability to move the eyes (ophthalmoparesis) asso- ciated with pupils that do not react to light or looking at near objects. Like the other forms of the Guillain Barre

syndrome, the Fisher syndrome is an acute monophasic autoimmune disorder that can follow infections. Like the other forms, it is likely that the immune response to antigens on infectious agents result in an immune attack on similar moieties within peripheral nerve molecular mimicry. In the Fisher syndrome, serologic studies have found the presence of antibodies against the ganglio- side GQ1b (Chiba et al. 1993; Willison et al. 1993), and experimental studies have shown that exposure to strains of Campylobacter jejuni, that bear related epitopes with their lipopolysaccharides, can produce pathogenic anti-GQ1b antibodies (Plomp et al. 1999). In the inflammatory demyelinating form of Guillain Barre syndrome treatment with plasmapheresis–the removal of the immunoglobulin fraction of plasma by exchange for albumin–or the infusion of large amounts of human immunoglobulin, a procedure that ameliorates many immune disorders, speeds recovery. Although no data applies specifically to the Fisher syndrome, it is reason- able to infer that these treatments would be efficacious in this disorder as well.

Whether the ataxic represents a ganglionopathy is unre- solved. Immunization of rabbits with GD1b produces an inflammatory ganglionopathy and ataxia (Kusunoki et al. 1999). However, the reversibility of the ataxia in the Fisher syndrome suggests that the ganglion cells need not be destroyed.

Toxic Causes

Several pharmacologic agents can produce ataxic neuropathies. Whether these are truly sensory gan- glionopathies is questionable. Some agents, such as pyridoxine, can produce loss of large DRG neurons experimentally, but the reversibility of the effects of intoxication by large doses of pyridoxine in man, sug- gests that it at least begins as a length-dependent axonal degeneration. Regeneration can occur when the agent is discontinued. Several can produce neuropathic pain, and experimental models of taxane-induced painful neuropathies have been developed.

References

1. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I (1993) Serum Anti-GQ1b Antibody is Associated with Oph- thalmoplegia in Miller Fisher Syndrome and Guillain-Barre Syndrome: Clinical and Immunohistochemical Studies. Neu- rology 43:1911–1917

2. Denny-Brown D (1948) Primary Sensory Neuropathy with Mus- cular Changes Associated with Carcinoma. J Neurol Neurosurg Psychiatry 11:73–87

3. Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, Feldman EL (1990) Ataxic Sensory Neuropathy and Dor- sal Root Ganglionitis Associated with Sjogren’s Syndrome. Ann Neurol 27:304û315

4. Kuntzer T, Antoine JC,Steck AJ (2004) Clinical Features and Pathophysiological Basis of Sensory Neuronopathies (Gan- glionopathies). Muscle Nerve 30:255–268

5. Kusunoki S, Hitoshi S, Kaida K, Arita M, Kanazawa I (1999) Monospecific Anti-GD1b IgG is Required to Induce Rabbit Ataxic Neuropathy. Ann Neurol 45:400–403

822 Gap Junctions

6. Lauria G, Pareyson D, Grisoli M, Sghirlanzoni A (2000) Clinical and Magnetic Resonance Imaging Findings in Chronic Sensory Ganglionopathies. Ann Neurol 47:104–109

7. Lauria G, Pareyson D, Sghirlanzoni A (2003) Neurophysiologi- cal Diagnosis of Acquired Sensory Ganglionopathies. Eur Neu- rol 50:146–152

8. Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D (2001) Epidermal Nerve Fiber Density in Sensory Ganglionopathies:

Clinical and Neurophysiologic Correlations. Muscle Nerve 24:1034–1039

9. Mellgren SI, Conn DL, Stevens JC, Dyck PJ (1989) Peripheral Neuropathy in Sjogren Syndrome. Neurology 39:390–394 10. Plomp JJ, Molenaar PC, O’Hanlon GM, Jacobs BC, Veitch J,

Daha MR, vanDoorn PA, van der Meche FGA, Vincent A, Mor- gan BP, Willison HJ (1999) Miller Fisher Anti-GQ1b Antibod- ies:α-Latrotoxin-Like Effects on Motor End Plates. Ann Neu- rol 45:189–199

11. Willison HJ, Veitch J, Patterson G, Kennedy PGE (1993) Miller Fisher Syndrome is Associated with Serum Antibodies to GQ1b Ganglioside. J Neurol Neurosurg Psychiatry 56:204–206 12. Windebank AJ, Blexrud MD, Dyck PJ, Daube JR, Karnes JL

(1990) The Syndrome of Acute Sensory Neuropathy: Clinical Features and Electrophysiologic and Pathologic Changes. Neu- rology 40:584–591

Gap Junctions

Definition

Gap junctions are intercellular channels established between cells through which small molecules can pass.

Within the spinal cord, the majority of gap junctions are found between astrocytes. Gap junctions allow for fast communication between cells over long distances. Due to this, gap junction communication may be salient to extra-territorial/ mirror-image pain.



Cord Glial Activation

Gastroesophageal Reflux Disease



GERD



Visceral Pain Model, Esophageal Pain

Gastrointestinal Tract, Nocifensive Behaviors



Nocifensive Behaviors, Gastrointestinal Tract

GAT 1, GAT 2, GAT 3

Definition

Plasma membrane GABA transporter, isoforms 1-3.



GABA and Glycine in Spinal Nociceptive Processing

Gate Control Theory

Definition

The Gate Control Theory was devised by Melzack and Wall in 1965. It proposed an explanation (later falsi- fied) on how innocuous stimulation inhibits pain via a presynaptic inhibitory mechanism. It was claimed that innocuous stimulation, such as produced by rubbing your skin, activates large sensory nerve fibers and in- hibits nociceptive neurons in the spinal cord. If small fiber nociceptive primary afferents are simultaneously being activated by a noxious stimulus such as a bee sting, less pain is felt because the “pain gate“ is closed.



Central Nervous System Stimulation for Pain



Pain Treatment, Spinal Cord Stimulation

Gazelius Model



Retrograde Cellular Changes after Nerve Injury

GBS



Guillain Barré Syndrome

GDNF



Glial Cell Line-Derived Neurotrophic Factor

GDNF-Dependent Neurons



IB4-Positive Neurons, Role in Inflammatory Pain

Gender

Definition

Gender is the psychosocial identity in males and females such as masculinity and femininity. It is both the person’s representation as male or female, and how that person is responded to by social institutions on the basis of the individual’s gender presentation. Gender refers to the so- cial, political and psychological aspects of what it means to live as male or female in a given society.



Gender and Pain



Psychological Aspects of Pain in Women

G

Gender and Pain 823

Gender and Pain

A

M. U

Health and Human Performance and Occupational Therapy, Dalhousie University, Halifax, NS, Canada aunruh@dal.ca

Definition

Gender and sex are often used interchangeably as if they were synonyms but they have different meanings. Sex refers to the anatomical, hormonal, and physiological differences associated with being male or female. Gen- der refers to the social, cultural, political and sometimes religious contexts in which humans are socialized to as- sume male and female roles. When differences between men and women occur it is tempting to ask whether these differences are because of sex or because of gender, but these factors are highly interactive. A biopsychosocial framework incorporating the interactive nature of sex and gender is necessary to examine men’s and women’s pain experience.

Characteristics

Sex difference (see

Sex Differences in Descending Pain Modulatory Pathways) in the prevalence of pain experience has been identified in many epidemiological studies (see LeReshe 2000). Women report more mi- graines, tension headaches, abdominal pain, facial/oral pain, pelvic pain and musculoskeletal pains (especially pain in the neck and shoulders). Women report more severe and more frequent pain and pain that is of longer duration. They are more likely to report pain due to mul- tiple sclerosis, cancer, reflex sympathetic dystrophy, irritable bowel syndrome, and carpal tunnel syndrome.

Other pains, such as pain due to sickle cell disease and post herpetic neuralgia, are more common in men.

Women have a greater physiological predisposition for pain due to differences in the actions of sex differences that affect neuroactive agents, opiate and non-opiate systems, nerve growth factor and the sympathic sys- tem (Berkley 1997; Holdcroft and Berkley 2006). The prevalence of migraines illustrates the contribution of biology to sex differences and also the complex influ- ence of hormones on women’s pain experience. Prior to puberty, the prevalence of migraine is similar for boys and girls and in some studies higher for boys.

Following puberty, prevalence sharply increases for females, remaining elevated throughout life even fol- lowing menopause, though rates decrease in the later life period. Nevertheless, some women experience mi- graines only during pregnancy while other women have reduced risk of migraine while pregnant. Hormonal effects can occur across the menstrual cycle. They can alter nociceptive responses in central and peripheral mechanisms, and can result in increased and sometimes

decreased pain sensitivity. The menstrual cycle also influences women’s sensitivity to experimental and clinical pains, with greater sensitivity often reported about the ovulation and the peri-menstrual period.

The contribution of biology is also evident in sex and species differences in response to analgesia (see Craft 2003; Fillingim and Ness 2000). In non-human species (mice and rats), greater opioid analgesia is found in males, but in the limited human literature, greater opioid analgesia is reported for women. Greater anal- gesia to cholinergic agents has been shown in women, as well as greater analgesic response to ibuprofen in men. These differences have only been examined in acute pain. Whether sex influences analgesic response to chronic administration of analgesics is currently unknown.

Studies of sex differences in the non-human literature also demonstrate the complexity of sex differences in ob- served pain behaviors and potential pain mechanisms.

Sex differences can be identified in basal nociception and morphine antinociception in rodents, but they ap- pear to be dependent on the genetic background of the rat or mouse being studied (Mogil 2000). The likelihood of observing sex differences in opioid analgesics in rats seems to increase as opioid efficacy (maximal analgesia) decreases. That is, sex differences may be related to the effectiveness of the opioid. While the sex of the animal is important, the type of animal, its genetic background, and the analgesic testing procedures also influence re- sponse to analgesics.

In addition to analgesic response, opioids may have other effects that may also be related to sex. In nonhumans, sex differences are found in respiration, blood pressure, body temperature, urination, nausea and vomiting, food intake, and locomotor activity in response to opioids.

These effects have not yet been examined by sex in the human population.

People have different expectations about males and fe- males in the way that they might typically respond to pain (Myers et al. 2001); these expectations are linked to cultural values about gender-related roles (Nayak et al. 2000). Women are often thought to be more emo- tional in response to pain and men to be more stoical.

The socialization of pain through gender-related expec- tations can be seen through studies about pain in child- hood (Unruh and Campbell 1999). Fathers expect that their sons will tolerate pain better than their daughters.

Children learn to express pain to mothers rather than to

fathers. Girls show more affective and behavioral dis-

tress in response to pain, even though their pain ratings

are often similar to boys. Men are expected to be more

stoical when they experience pain, and may be treated

more seriously when they do complain of pain. Attrac-

tiveness of patients, particularly women, also matters. A

more attractive person is perceived to have less pain and

to be able to cope with pain better than someone who is

not attractive (Hadjistavropoulos et al. 1996).

824 Gender and Pain

There are a number of studies showing that males and females are not treated in the same way for pain, with women receiving more psychological explanations for their pain, less pain medication and more sedatives (see Hoffmann and Tarzian 2001; Unruh 1996). Such differ- ential treatment on the basis of gender may occur even in childhood. Women are also less likely to be referred to a pain clinic, and when they are referred for rehabilita- tion services, they are less likely to receive services that facilitate employment. Such studies demonstrate that the effect of gender in pain management is more often to the detriment of women, but two earlier studies found that women received more powerful analgesics for pain due to cancer than did men, and while men made more requests for pain medication, women received medi- cation. Taken together, these studies demonstrate that social judgments and expectations about how men and women ought to behave when they are in pain can influ- ence the nature of the pain assessment and management they receive, but the impact can be variable.

Social expectations pose certain risks for women and men. Women are more inclined to discuss their emo- tional response to pain and may receive more psycholog- ical explanations (as causal and contributory explana- tions) for their pain. They may be offered more psycho- logical interventions and fewer medical, physical and pharmacological treatments. Men are more likely not to comment on emotional aspects of their pain, and hence receive fewer psychological interventions and more in- vasive medical, physical and pharmacological interven- tions. Assessment and management is biased by social expectations about gender and pain in either case, and may result in inadequate pain relief and disability reduc- tion.

There is little evidence that women and men worry dif- ferently about pain, but women may attend to pain sooner and they do appear to have some important coping differ- ences (Robinson et al. 2000). Women worry about pain and its interference on activities more readily. They de- velop a greater repertoire of coping strategies per pain event, and they use more social support and more health care to manage pain. The use of social support is consis- tent with women’s tendency to use more social support for other, non-pain related health concerns.

The possible effect of sex and gender on pain response can be observed in the experimental pain literature.

Women and men are often similar in their pain re- sponses, but when they differ, men report higher pain thresholds, higher pain tolerance and lower pain inten- sity ratings. There is limited experimental pain research in pediatric pain, but it does suggest that these differ- ences may begin in the school-age years. Interestingly, if the initial noxious stimulus is more severe, for exam- ple if the temperature of the cold water is lowered, then sex differences may be eliminated. The influence of gender can be seen in the way that participants respond to experimenter gender and to manipulation of social

variables in experimental research. When male and female experimenters wear clothing that accentuates their masculinity or femininity, they alter the responses of male subjects but not females. Similarly, changing social expectations in the study design tends to alter significantly the pain responses of male subjects, with some variation among the female subjects but to a lesser and usually non-significant extent.

While researchers have tended to emphasize sex and gender differences in pain experience in basic science research, experimental research, and in clinical pain research, there is considerable within group variation.

Virtually nothing is known about these within group differences and why they might occur. There are likely to be important factors that contribute to within group differences that need to be better understood, partic- ularly with respect to pain management both from a biological and a psychosocial perspective.

There is some debate about whether boys and girls, men and women should be treated differently when they are seen for pain. There is very little evidence to indicate that one gender is better than the other in coping with chronic pain, but there is suggestive evidence that they tend to cope with pain differently. Girls and women tend to talk about emotional aspects of pain, and may find the social support and information seeking inherent in this discus- sion to be helpful. It is possible that the greater risk to catastrophize in response to pain for women would be re- duced by an emphasis on cognitive-behavioral interven- tions, in addition to other pain management strategies for girls and women. It is possible that the same argument is pertinent to catastrophizing in males. However, discus- sions about psychological aspects of pain with boys and men may require gender specific strategies to reduce the social expectation of stoicism. Nevertheless, it is possi- ble that the social expectation of stoicism in males has some benefit in reducing their risk of pain-related dis- ability. The existing research about sex differences in re- sponse to analgesics suggests that perhaps males and fe- males should be managed differently, but the research is too preliminary to come to this conclusion (Miaskowski et al. 2000). Further research is needed to explore biolog- ical and psychological mechanisms of sex differences in pain response to analgesics and the circumstances in which they may or may not occur. In addition, within group differences of pain response to analgesics must be better understood.

The previous ten years have seen considerable advance- ment in sex and gender in pain research. In another five to ten years, the mechanisms of these differences and their impact on pain assessment and management will be better understood.

References

1. Berkley KJ (1997) Sex Differences in Pain. Behav Brain Sci 20:371–380

G

Gene Transcription 825

2. Craft RM (2003a) Sex Difference in Opioid Analgesia: “From Mouse to Man”. Clin J Pain 19:175–186

3. Craft RM (2003b) Sex Differences in Drug– and Non-Drug- Induced Analgesia. Life Sci 72:2675–2688

4. Fillingim RB, Maixner W (1995) Gender Differences in the Re- sponses to Noxious Stimuli. Pain Forum 4:209–221

5. Fillingim RB, Ness TJ (2000) Sex-Related Hormonal Influ- ences on Pain and Analgesic Responses. Neurosci Biobehav Rev 24:485û501

6. Hadjistavropoulos T, McMurty B, Craig KD (1996) Beautiful Faces in Pain: Biases and Accuracy in the Perception of Pain.

Psychol Health 11:411–420

7. Hoffman DE, Tarzian AJ (2001) The Girl Who Cried Pain:

A Bias Against Women in the Treatment of Pain. J Law Med Ethics 29:13–27

8. Holdcroft A, Berkley KJ (2006) Sex and Gender Differences in Pain and its Relief. In: McMahon SB, Koltzenburg M (eds) Wall & Melzack’s Textbook of Pain, 5^thed, Elsevier Chuchill Livingston, Edinburgh, pp 11181–1197

9. LeReshe L (2000) Epidemiologic Perspectives. In: Fillingim RB (ed) Sex, Gender, and Pain. IASP Press, Seattle, pp 233–249 10. Miaskowski C, Gear RW, Levine JD (2000) Sex-Related Dif-

ferences in Analgesic Responses. In: Fillingim RB (ed.) Sex, Gender, and Pain. IASP Press, Seattle, p 209–230

11. Mogil JS (2000) Interactions between Sex and Genotype in the Mediation and Modulation of Nociception in Rodents. In:

Fillingim RB (ed) Sex, Gender, and Pain. IASP Press, Seattle, pp 25–40

12. Myers CD, Papas RK, Emily EA, Waxenberg LB, Fillingim RB, Robinson ME, Riley JL (2001) Gender Role Expectations of Pain:

Relationship to Sex Differences in Pain. J Pain 2:251–257 13. Nayak S, Shiflett SC, Eshun S, Levine FM (2000) Culture and

Gender Effects in Pain Beliefs and the Perception of Pain Tol- erance. Cross-Cultural Research 34:135–151

14. Robinson ME, Riley JL, Myers CD (2000) Psychosocial Con- tributions to Sex-Related Differences in Pain Responses. In:

Fillingim RB (ed) Sex, Gender, and Pain. IASP Press, Seattle, pp 41–68

15. Unruh AM (1996) Gender Variations in Clinical Pain Experience.

Pain 65:123–167

16. Unruh AM, Campbell MA (1999) Gender Variation in Children’s Pain Experiences. In: McGrath PJ, Finley GA (eds) Chronic and Recurrent Pain in Children and Adolescents. Prog Pain Res Man- age 13:199–241

17. Wizemann TM, Pardue ML (2001) Exploring the Biological Con- tributions to Human Health. Does Sex Matter? National Academy Press, Washington

Gender Differences in Opioid Analgesia



Sex Differences in Opioid Analgesia

Gender Role Expectation of Pain Scale

Synonym GREP Scale Definition

The Gender Role Expectation of Pain Scale measures sex-related stereotypic attributions of pain sensitivity, endurance, and willingness to report pain.



Psychological Aspects of Pain in Women

Gender Role Theories in Pain

Definition

Gender role theories in pain suggest that women and men are socialized to respond differently to pain. Masculinity is stereotypically associated with stoicism, and feminin- ity is stereotypically associated with increased sensitiv- ity.



Psychological Aspects of Pain in Women

Gene

Definition

A gene contains hereditary information encoded in the form of DNA and is located at a specific position on a chromosome in a cell’s nucleus. Genes individually de- termine many aspects of physiological functions by con- trolling the production of proteins.



NSAIDs, Pharmacogenetics

Gene Array

Definition

Nucleic acid arrays work by hybridization of labeled RNA or DNA in solution to DNA molecules attached at specific locations on a surface. The hybridization of a sample to an array is, in effect, a highly parallel search by each molecule for a matching partner on an ’affin- ity matrix’, with the eventual pairings of molecules on the surface determined by the rules of molecular recognition.



Retrograde Cellular Changes after Nerve Injury

Gene Therapy and Opioids



Opioids and Gene Therapy

Gene Transcription

Definition

Gene transcription is the process of constructing a mes- senger RNA molecule using a DNA molecule as a tem- plate, with resulting transfer of genetic information to the messenger RNA.



NSAIDs, Pharmacogenetics

826 General Adaptation Syndrome

General Adaptation Syndrome



Postoperative Pain, Pathophysiological Changes in Neuro-Endocrine Function in Response to Acute Pain

General Anesthesia

Definition

General Anesthesia is a drug-induced loss of conscious- ness during which patients are not arousable, and often have impaired cardiorespiratory function needing sup- port.



Pain and Sedation of Children in the Emergency Set- ting

Generator Currents

Definition

Membrane currents originated at the membrane of sen- sory receptor endings when transduction channels are open or closed by the stimulus. These currents spread passively from the stimulated membrane patch to neigh- bor sites (electrotonic propagation) according to the spa- tial and temporal cable properties of the axon.



Nociceptor Generator Potential

Generic Carbamazepine



Tegretol

Genetic Correlation

Definition

Genetic Correlation is a mediation by similar sets of genes, suggestive of overlapping physiological medi- ation. Genetic correlation of two traits can be inferred by a significant correlation of inbred strain means on each trait.



Heritability of Inflammatory Nociception

Genetic Factors Contributing to Opioid Analgesia



Opioid Analgesia, Strain Differences

Genetic Linkage

Definition



Heritability of Inflammatory Nociception



Quantitative Trait Locus Mapping

Geniculate Neuralgia

Synonyms

Facial ganglion neuralgia Definition

Pain paroxysms felt in the depth of the ear, lasting for seconds or minutes, or intermittent occurrence associ- ated with injury or dysfunction of the seventh cranial nerve (facial nerve) via the nervus intermedius (of Wris- berg)are known as facial (geniculate) ganglion neural- gia.



Neuralgias



Neuralgia, Assessment



Tic and Cranial Neuralgias



Trigeminal, Glossopharyngeal, and Geniculate

Genital Mucosa, Nociception



Nociception in Mucosa of Sexual Organs

Genome

Definition

A genome is the total set of genes carried by an individ- ual or a cell. The genome determines, in part, the final morphology or body or form of the individual human or cell.



Cell Therapy in the Treatment of Central Pain

Genotype

Definition

The genotype describes the genetic makeup of an indi- vidual organism, determined by the full complement of genes that organism possesses.



NSAIDs, Pharmacogenetics

Genotypic Influences on Opioid Analgesia



Opioid Analgesia, Strain Differences