Sex differences in the contributions of spinal atypical PKCs and downstream targets to the maintenance of nociceptive sensitization

Abstract

Background: Chronic pain has been shown to depend on nociceptive sensitization in the spinal cord, and while multiple mechanisms involved in the initiation of plastic changes have been established, the molecular targets which maintain spinal nociceptive sensitization are still largely unknown. Building upon the established neurobiology underlying the maintenance of long-term potentiation in the hippocampus, this present study investigated the contributions of spinal atypical protein kinase C (PKC) isoforms PKCi/k and PKMf and their downstream targets (p62/GluA1 and NSF/GluA2 interactions, respectively) to the maintenance of spinal nociceptive sensitization in male and female rats. Results: Pharmacological inhibition of atypical PKCs by ZIP reversed established allodynia produced by repeated intramuscular acidic saline injections in male animals only, replicating previously demonstrated sex differences. Inhibition of both PKCi/k and downstream substrates p62/GluA1 resulted in male-specific reversals of intramuscular acidic saline-induced allodynia, while female animals continued to display allodynia. Inhibition of NSF/GluA2, the downstream target to PKMf, reversed allodynia induced by intramuscular acidic saline in both sexes. Neither PKCi/k, p62/GluA1 or NSF/GluA2 inhibition had any effect on formalin response for either sex. Conclusion: This study provides novel behavioural evidence for the male-specific role of PKCi/k and downstream target p62/GluA1, highlighting the potential influence of ongoing afferent input. The sexually divergent pathways underlying persistent pain are shown here to converge at the interaction between NSF and the GluA2 subunit of the AMPA receptor. Although this interaction is thought to be downstream of PKMf in males, these findings and previous work suggest that females may rely on a factor independent of atypical PKCs for the maintenance of spinal nociceptive sensitization.

Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain

“…And more notably, recent studies provide novel behavioral evidence that there is a sex difference in PKMζ involved in the maintenance of nociceptive sensitization. Pharmacological inhibition or genetic ablation of PKMζ effectively reduced referred visceral and muscle pain in males, but not in female mice and rats [62,63]. These findings suggest that females may rely on a factor independent of PKMζ for the maintenance of nociceptive sensitization.…”

Qualitative sex differences in pain processing: emerging evidence of a biased literature

“…Recent findings demonstrating these qualitative sex differences are shown in TABLe 1 and illustrate that sex dependence can be found at all levels of the neuraxis and in many different types of proteins. In most cases, the evidence for a sex-specific role for a mediator comprises significant effects on pain produced by the neurochemical itself in one sex but not the other [94][95][96][97][98][99] , effects on pain of receptor antagonism in one sex but not the other 61,98,[100][101][102][103][104] and/or significant pain phenotypes in transgenic animals in which the gene encoding the neurochemical or its receptor is mutated compared with the wild type in one sex but not the other 67,68,[70][71][72] . Likely to be particularly relevant to humans is the observation 94 that calcitonin gene-related peptide (CGRP) applied to the dura produces mechanical pain hypersensitivity and priming in female but not male rats and mice, since CGRP and its receptor are the molecular targets of recently approved migraine drugs 105 .…”