Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans

Abstract

Highlights d Re-exposure to a context associated with pain results in pain hypersensitivity d Conditioned pain sensitivity is only present in males via testosterone d The phenomenon can be demonstrated in both mice and humans d The phenomenon is dependent on stress and blocked by zeta inhibitory peptide (ZIP) SUMMARYPain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mz isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.Detailed methods are provided in the online version of this paper and include the following:TABLE d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS B Animal Subjects B Human Participants d METHOD DETAILS B Animal Experiments B Human Experiments d QUANTIFICATION AND STATISTICAL ANALYSIS SUPPLEMENTAL INFORMATION Supplemental Information includes one data file and five figures and can be found with this article online at https://doi.

Sex differences in reward- and punishment-guided actions

“…Our results from the AAT suggest two related hypotheses: (1) females may be more resilient than males to an acute aversive event, and (2) continued experience of the aversive context may lead to increased anxiety in females, but not males. The first of these is consistent with the results of a study by Martin et al (2019) that showed that re-exposure to a context associated with pain results in pain hypersensitivity in male mice, but not female mice, and similarly in humans, that men, but not women, self-reported high levels of stress in a context previously associated with tonic pain (L. J. Martin et al, 2019). Considering these findings in interpreting our current results, it is possible that males responded more strongly to the aversive experience after re-exposure in our AAT.…”

Transcriptomic sex differences in sensory neuronal populations of mice

“…Based on our findings, we favor the hypothesis that sex differences in nociception may be partially based on DEGs in female and male sensory neurons. Our results advance our understanding of sex dimorphisms in nociceptive pathways and provide an informatic basis for further studies on regulation of sexdependent gene expression plasticity in sensory neurons regulated by injury and/or by gonadal hormones 44,87,88 .…”

“…www.nature.com/scientificreports/ Groups of female-predominant DEGs generated from Percoll purified DRG and TG neurons, and skin or thigh innervating L3-L5 DRG neurons showed low overlap. The highest numbers (593) of such DEGs (RPKM > 1; FC > 2; Pval < 0.05) were identified in Percoll purified TG neurons, and the lowest (88) were in DRG neurons innervating skin and thigh (Figs. 3C,8A).…”

<p>Sex and Gender are Not the Same: Why Identity Is Important for People Living with HIV and Chronic Pain</p>

“…However, emerging evidence suggests that psychosocial factors can modulate pain in rodents in ways that mirror human interactions. 43,44 Social and cultural factors can alter pain experience. Women with chronic pain report greater hostility and dismissal 45 and are more likely to have their pain attributed to psychological issues.…”