Abstract
Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E2 (PGE2) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz−/− mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain.
Highlights
Chronic pain is more prevalent in women than men (Andersson et al, 1993; Myers et al, 2003; Racine et al, 2012)
Prkcz−/− mice bred slowly and had small litters, so a limited number of mice were generated for these experiments. When both sexes were considered together, there was no difference in nerve growth factor (NGF)-induced mechanical hypersensitivity (Fig. 1A) or the response to the second stimulus, prostaglandin E2 (PGE2) (Fig. 1B), between genotypes
When considering males alone, while there was no difference between genotypes in NGF-induced mechanical hypersensitivity, there was a statistically significant difference in the response to the second stimulus (Fig. 1C and D). This finding is consistent with previous studies using a different Prkcz−/− mouse line and is in line with pharmacological manipulation of atypical PKC (aPKC) in the spinal cord wherein an effect is only seen in male rodents (Nasir et al, 2016; George et al, 2019; Martin et al, 2019)
Summary
Chronic pain is more prevalent in women than men (Andersson et al, 1993; Myers et al, 2003; Racine et al, 2012). Recent NIH initiatives (Collins and Tabak, 2014) requiring mixed-sex animal testing have encouraged the discovery of sex-specific pain mechanisms that may underlie differences between males and females One of the best examples identified to date is the dominant role of microglia in chronic nociceptive hypersensitivity in males (Taves et al, 2016). Recent work suggests these sex-specific mechanisms in the monocyte lineage may be preserved in human patients with neuropathic pain (North et al, 2019). It is of critical importance to understand how chronic pain develops in females in order to develop effective pain therapeutics for women (Storesund et al, 2016; Chow et al, 2017)
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