In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?" Keywords Sex differences; Gonadal hormones; Estrogens The case for studying sex and gender differences in pain and analgesiaThe pain field has moved from debating whether sex differences in pain exist to recognizing the importance of these differences. Attention is now directed toward understanding (1) what conditions lead to the expression of sex and gender differences in pain experience and reactivity, (2) what mechanisms underlie these differences, and (3) how these differences can inform clinical management of pain.As noted in a recent review, at least 79% of animal studies published in Pain over the preceding 10 years included male subjects only, with a mere 8% of studies on females only, and another 4% explicitly designed to test for sex differences (the rest did not specify) [142]. Given the substantially greater prevalence of many clinical pain conditions in women vs. men [20,199], and growing evidence for sex differences in sensitivity to experimental pain and to analgesics [21,41,213], we recommend that all pain researchers consider testing their hypotheses in both sexes, or if restricted by practical considerations, only in females. It is invalid to assume that data obtained in male subjects will generalize to females, and the best non-human model of the modal human pain sufferer -a woman -is a female animal. If only males are examined in a given study, it is important that a rationale for exclusion of females be provided and that the potential limitation in generalizability of the findings be addressed in the discussion, particularly when examining a pain phenomenon that occurs with greater prevalence or severity in females. In both preclinical and clinical studies, a comparison of both sexes will further our understanding of individual differences in sensitivity to pain and analgesia, thus improving our ability to treat and prevent pain in all people. General considerationsTwo issues of terminology are important. First, the term "sex" refers to biologically based differences, while the term "gender" refers to socially based phenomena. Although biological sex exerts a major influence on one's gender identity, sex and gender a...

The incidence of chronic pain is estimated to be 20–25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.

Sensitization of primary afferent neurons underlies much of the pain and tenderness associated with tissue injury and inflammation. The increase in excitability is caused by chemical agents released at the site of injury. Because recent studies suggest that an increase in voltagegated Na+ currents may underlie increases in neuronal excitability associated with injury, we have tested the hypothesis that a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa), selectively expressed in a subpopulation of sensory neurons with properties of nociceptors, is a target for hyperalgesic agents. Our results indicate that three agents that produce tenderness or hyperalgesia in vivo, prostaglandin E2, adenosine, and serotonin, modulate TTX-R INa. These agents increase the magnitude of the current, shift its conductance-voltage relationship in a hyperpolarized direction, and increase its rate of activation and inactivation. In contrast, thromboxane B2, a cyclooxygenase product that does not produce hyperalgesia, did not affect TTX-R INa. These results suggest that modulation of TTX-R INa is a mechanism for sensitization of mammalian nociceptors.Nociceptors are primary afferent neurons that respond to noxious or potentially tissue-damaging stimuli and are unique among sensory neurons because they can be sensitized. The decrease in threshold and increase in the response to a constant stimulus that are characteristic of nociceptor sensitization are thought to underlie the hyperalgesia or tenderness associated with tissue injury. Agents released at the site of tissue injury sensitize nociceptors by initiating a cascade of events (1) that likely results in a change in ionic conductances of the nociceptor peripheral terminal.Recent observations suggest that an increase in a voltagegated Na+ current might underlie the increased excitability of primary afferent neurons following injury. (i) The density of voltage-gated Na+ channels increases in a locus of hyperexcitability after nerve injury (2). (ii) Nerve injury induces an increase in the mRNA encoding three distinct voltage-gated Na+ channels (3). (iii) Nerve growth factor, an agent released at sites of injury (4), has been shown to increase expression of a number of voltage-gated Na+ channels in sensory neurons. An increase in the expression of Na+ channel mRNA would be expected to result in an increase in Na+ channel density and consequently in Na+ current. Thus, we hypothesized that hyperalgesic agents such as prostaglandin B2 (PGE2), serotonin (5-HT), and adenosine sensitize primary afferent nociceptors by increasing a voltage-gated Na+ current. Specifically, we hypothesized that since a tetrodotoxin (TTX)-resistant voltage-gated Na+ current (TTX-R INa) appears to be selectively expressed in nociceptive afferents (5), this current is a target for modulation by hyperalgesic agents.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solel...

A tetrodotoxin-resistant voltage-gated Na ϩ current (TTX-R I Na ) appears to be the current primarily responsible for action potential generation in the cell body and terminals of nociceptive afferents. Although other voltage-gated Na ϩ currents are modulated by the activation of protein kinase C (PKC), protein kinase A (PKA), or both, the second messenger pathways involved in the modulation of TTX-R I Na are still being defined. We have examined the modulation of TTX-R I Na in isolated sensory neurons with whole-cell voltage-clamp recording. Activation of either PKC or PKA increased TTX-R I Na . PKA activation also produced a leftward shift in the conductancevoltage relationship of TTX-R I Na and an increase in the rates of current activation, deactivation, and inactivation. Inhibitors of PKC decreased TTX-R I Na , whereas inhibitors of PKA had no effect on the current. Investigating the interaction between PKC and PKA revealed that although inhibitors of PKA had little effect on PKC-induced modulation of TTX-R I Na , inhibitors of PKC significantly attenuated PKA-induced modulation of the current. Finally, although PGE 2 -induced modulation of TTX-R I Na was more similar to PKA-induced modulation of the current than to PKC-induced modulation, PGE 2 -induced effects were inhibited by inhibitors of both PKC and PKA. Thus, although TTX-R I Na is a common target for cellular processes involving the activation of either PKA or PKC, PKC activity is necessary to enable subsequent PKA-mediated modulation of TTX-R I Na . Key words: dorsal root ganglion; inflammatory mediator; nociception; pain; primary afferent; second-messengerStudies of voltage-gated sodium currents (VGSC s) indicate that VGSC isoforms may be differentially modulated by protein kinase C (PKC) and protein kinase A (PK A). For example, a VGSC from brain tissue is decreased by the concurrent activation of PKC and PK A (Gershon et al., 1992;Li et al., 1992; Cantrell et al., 1996 Cantrell et al., , 1997, and a VGSC from cardiac muscle is decreased by PKC activation (Qu et al., 1994) and increased by PK A activation (Frohnwieser et al., 1995(Frohnwieser et al., , 1997. That these changes in VGSCs are physiologically relevant is suggested by the observations that receptor-mediated changes in cellular excitability reflect, at least in part, PKC -and /or PK A-mediated changes in VGSCs.We and others have recently demonstrated that a tetrodotoxinresistant voltage-gated Na ϩ current (TTX-R I Na ), expressed primarily in nociceptive afferents, is modulated by hyperalgesic inflammatory mediators in a manner that is likely to enhance nociceptor excitability (England et al., 1996;Gold et al., 1996b; Cardenas et al., 1997). Although there is evidence both for (England et al., 1996) and against (C ardenas et al., 1997) a role for protein kinase A in the modulation of TTX-R I Na , the contribution of PKC has yet to be investigated.Using agents that activate or inhibit PKC and PK A, we have tested the hypothesis that these kinases are involved in the modulation of T...

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The underlying mechanisms of neuropathic pain are poorly understood, and existing treatments are mostly ineffective. We recently demonstrated that antisense mediated "knock-down" of the sodium channel isoform, Na(V)1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Na(V)1.8 in the neuropathic state. Here we have investigated mechanisms through which Na(V)1.8 contributes to the expression of experimental neuropathic pain. Na(V)1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in Na(V)1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in Na(V)1.8 immunoreactivity along the sciatic nerve. The distribution of Na(V)1.8 reflected predominantly the presence of functional channels in unmyelinated axons. The C-fiber component of the sciatic nerve compound action potential (CAP) was resistant (>40%) to 100 microm TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 microm TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of Na(V)1.8 with antisense oligodeoxynucleotides prevented the redistribution of Na(V)1.8 in the sciatic nerve and reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. They also suggest that blocking Na(V)1.8 would be an effective treatment of neuropathic pain.

Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, resulted in a time-dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective "knock-down" of the expression of NaV1.8, and a reduction in the slow-inactivating, TTX-resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non-noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.

Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha2delta1 subunit (Ca(v)alpha2delta1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Ca(v)alpha2delta1 in neuronal tissues. Ca(v)alpha2delta1 overexpression resulted in enhanced currents, altered kinetics and voltage-dependence of VGCC activation in sensory neurons; exaggerated and prolonged dorsal horn neuronal responses to mechanical and thermal stimulations at the periphery; and pain behaviors. However, the transgenic mice showed normal dorsal horn neuronal responses to windup stimulation, and behavioral responses to tissue-injury/inflammatory stimuli. The pain behaviors in the transgenic mice had a pharmacological profile suggesting a selective contribution of elevated Ca(v)alpha2delta1 to the abnormal sensations, at least at the spinal cord level. In addition, gabapentin blocked VGCC currents concentration-dependently in transgenic, but not wild-type, sensory neurons. Thus, elevated neuronal Ca(v)alpha2delta1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.