Background
Chronic pain of neuropathic nature after spinal cord injury (SCI) is common and its underlying mechanisms are poorly understood. Genes, as well as sex, have been implicated, but not ...thoroughly investigated in experimental genetic models for complex traits. We have previously found that inbred Dark‐Agouti (DA) rats develop more severe SCI pain‐like behaviour than a major histocompatibility complex‐congenic Piebald Virol Glaxo (PVG)‐RT1av1 strain in a model of photochemically induced SCI.
Methods
In this study, a genome‐wide linkage study in an F2 cross between the susceptible DA and resistant PVG‐RT1av1 strains was performed in order to explore the influence of genes and sex for SCI pain.
Results
A consistent finding was that female rats in parental, F1 and F2 generations displayed increased pain sensitivity at testing before injury and also developed mechanical hypersensitivity more rapidly and to a greater extent than male rats. In addition, we could identify three quantitative trait loci (QTLs) associated with pain‐like behaviour: a sex‐specific QTL on chromosome 2, one on chromosome 15 and on chromosome 6. Animals carrying DA alleles at each of these loci were more susceptible to development of mechanical hypersensitivity compared with rats with PVG alleles.
Conclusion
This is the first whole genome QTL mapping of neuropathic pain‐like behaviour in a model of SCI. The results provide strong support for a significant genetic and sex component in development of pain after SCI and provide the basis for further genetic dissection and positional cloning of the underlying genes.
Following peripheral axotomy, long-lasting changes in the expression of neuropeptides and their receptors in primary sensory neurons are observed. These changes involve the downregulation of the ...excitatory peptides substance P and calcitonin gene-related peptide and the upregulation of the inhibitory peptides neuropeptide tyrosine and galanin, resulting in a reduction of transmission in the dorsal horn. The changes observed are thought to represent adaptive responses to limit the consequences of peripheral nerve damage to the organism as a whole and to promote survival and recovery of the individual neuron.
Abstract Here we studied the role of peripheral adenosine A2A receptors in mechanical hyperalgesia during inflammation using mice lacking the A2A receptors. Unilateral s.c. administration of the ...local inflammatory agent λ-carrageenan induced profound mechanical hyperalgesia 24 h after administration in the ipsilateral hind paw in wild-type mice. In homozygous mice lacking the A2A receptors, carrageenan-induced hyperalgesia was significantly reduced compared to wild type controls. The reduction in inflammatory hyperalgesia seen in A2A receptor knock-out mice was not associated with changes in paw edema. CGS 21680, a selective A2A receptor agonist, produced significantly more mechanical hyperalgesia in wild type females than in wild type males upon direct s.c. injection into the hindpaw whereas it had no effect upon systemic administration. The hyperalgesic effect of CGS 21680 was markedly reduced in the A2A knock-out mice of both sexes. Subcutaneous ZM-241,385, a selective A2A receptor antagonist, injected into the hindpaw reduced the mechanical hyperalgesia following carrageenan in female mice, but not in males. The results indicate that activation of peripheral adenosine A2A receptors during inflammation is associated with mechanical hyperalgesia, and that this effect is more prominent in females than in males.
Neuropeptides represent the most diverse family of neurotransmitters counting numerous members and even more G protein-coupled receptors, all of which are potential targets for drug development. ...Here, we focus on galanin and its three receptors by describing their possible involvement in pain and regeneration. Although animal experiments indicate that galanin, together with other molecules, may act as an endogenous system protecting against pain and improving nerve growth, these results have so far not been translated into patient treatments.
Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the ...preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics.
Abstract
A number of studies have demonstrated a higher prevalence of chronic pain states and greater pain sensitivity among women compared with men. Pain sensitivity is thought to be mediated by ...sociocultural, psychological, and biological factors.
This article reviews laboratory studies that provide evidence of sex differences in pain sensitivity and the response to analgesic drugs in animals and humans. The biological basis of such differences is emphasized.
The literature from this relatively new field was surveyed, and studies that clearly illustrate the differences in pain mechanisms between the sexes are presented. Using the search terms
sex, gender, and
pain, a review was conducted of English-language literature published on MEDLINE between January 1980 and August 2004.
Although differences in pain sensitivity between women and men are partly attributable to social conditioning and to psychosocial factors, many laboratory studies of humans have described sex differences in sensitivity to noxious stimuli, suggesting that biological mechanisms underlie such differences. In addition, sex hormones influence pain sensitivity; pain threshold and pain tolerance in women vary with the stage of the menstrual cycle. Imaging studies of the brain have shown differences between men and women in the spatial pattern and intensity of response to acute pain. Among rodents, females are more sensitive than males to noxious stimuli and have lower levels of stress-induced analgesia. Male rodents generally have stronger analgesic response to μ-opioid receptor agonists than females. Research on transgenic mice suggests that normal males have a higher level of activity in the endogenous analgesic system compared with normal females, and a human study has found that μ-receptors in the healthy female brain are activated differently from those in the healthy male brain. The response to κ-opioids, which is mediated by the melanocortin-1 receptor gene in both mice and humans, is also different for each sex.
Continued research at the genetic and receptor levels may support the need to develop gender-specific drug therapies.
The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the ...present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (
Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition,
Galr1 knock-out (
Galr1
−/−) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between
Galr1
−/− and wild type (
Galr1
+/+) mice, whereas the cold response was moderately enhanced in
Galr1
−/− mice. Both
Galr1
−/− mice and
Galr1
+/+ controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in
Galr1
−/−. The
Galr1
−/− mice and
Galr1
+/+ mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush.
The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.
Autotomy behavior is frequently observed in rats and mice in which the nerves of the hindlimb are severed, denervating the paw. This is the neuroma model of neuropathic pain. A large body of evidence ...suggests that this behavior reflects the presence of spontaneous dysesthesia and pain. In contrast, autotomy typically does not develop in partial nerve injury pain models, leading to the belief that these animals develop hypersensibility to applied stimuli (allodynia and hyperalgesia), but not spontaneous pain. We have modified the widely used Chung (spinal nerve ligation SNL) model of neuropathic pain in a way that retains the fundamental neural lesion, but eliminates nociceptive sensory cover of the paw. These animals performed autotomy. Moreover, the heritable across strains predisposition to spontaneous pain behavior in this new proximal denervation model (SNN) was highly correlated with pain phenotype in the neuroma model suggesting that the pain mechanism in the two models is the same. Relative reproducibility of strain predispositions across laboratories was verified. These data indicate that the neural substrate for spontaneous pain is present in the Chung-SNL model, and perhaps in the other partial nerve injury models as well, but that spontaneous pain is not expressed as autotomy in these models because there is protective nociceptive sensory cover.
Background
Nerve injury-triggered hyperexcitability in primary sensory neurons is considered a major source of chronic neuropathic pain. The hyperexcitability, in turn, is thought to be related to ...transcriptional switching in afferent cell somata. Analysis using expression microarrays has revealed that many genes are regulated in the dorsal root ganglion (DRG) following axotomy. But which contribute to pain phenotype versus other nerve injury-evoked processes such as nerve regeneration? Using the L5 spinal nerve ligation model of neuropathy we examined differential changes in gene expression in the L5 (and L4) DRGs in five mouse strains with contrasting susceptibility to neuropathic pain. We sought genes for which the degree of regulation correlates with strain-specific pain phenotype.
Results
In an initial experiment six candidate genes previously identified as important in pain physiology were selected for in situ hybridization to DRG sections. Among these, regulation of the Na+ channel α subunit Scn11a correlated with levels of spontaneous pain behavior, and regulation of the cool receptor Trpm8 correlated with heat hypersensibility. In a larger scale experiment, mRNA extracted from individual mouse DRGs was processed on Affymetrix whole-genome expression microarrays. Overall, 2552 ± 477 transcripts were significantly regulated in the axotomized L5DRG 3 days postoperatively. However, in only a small fraction of these was the degree of regulation correlated with pain behavior across strains. Very few genes in the “uninjured” L4DRG showed altered expression (24 ± 28).
Conclusion
Correlational analysis based on in situ hybridization provided evidence that differential regulation of Scn11a and Trpm8 contributes to across-strain variability in pain phenotype. This does not, of course, constitute evidence that the others are unrelated to pain. Correlational analysis based on microarray data yielded a larger “look-up table” of genes whose regulation likely contributes to pain variability. While this list is enriched in genes of potential importance for pain physiology, and is relatively free of the bias inherent in the candidate gene approach, additional steps are required to clarify which transcripts on the list are in fact of functional importance.
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