Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

Abstract

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn (SDH), direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund′s Adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and NMDA receptor potentiation within SDH neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator, BDNF, failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B, and pGluN2B) in female rats, resulting in no effect of ex vivo BDNF on synaptic NMDA receptor responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in SDH neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDA receptor potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β

“…Because BDNF is not necessary for the development of allodynia in female rodents ( 27 ), the mediator released from adaptive immune cells remains to be determined. Similar findings have been found in the Freund's adjuvant in vivo model of inflammatory pain in rodents and confirmed in human neurons ( 33 ). These authors also showed that ex vivo BDNF enhanced synaptic NMDA receptor responses in lamina I neurons from males but not from females and that ovariectomy eliminated these differences.…”

“…Neuropathic pain is seen more frequently in women than in men ( 29 ) and it is now recognized that understanding of divergent pain mechanisms in males vs. females is crucial to the development of appropriate therapeutic approaches ( 28 , 33 , 450 , 451 ).…”

“…Investigations over the last 15 years or so have started to unravel cellular and molecular mechanisms that may contribute to this difference ( 29 , 31 – 33 , 452 , 453 ). For example, microglia are not required for mechanical sensitivity to pain in female mice which require activation of adaptive immune cells such as T-lymphocytes ( 27 , 320 ).…”

“…Neuropathic components also contribute to pain associated with COVID-19, multiple sclerosis, fibromyalgia, migraine, osteoarthritis, rheumatoid arthritis, autoimmune disease, and complex regional pain syndromes (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Although the signs and symptoms of neuropathic pain are similar in males and females, it is now well-established that the underlying cellular mechanisms are very different (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Unlike nociceptive pain, which signals and protects an individual from tissue injury, neuropathic pain persists long after tissue healing and recovery has taken place (2).…”

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

“…Macrophage invasion of DRG is predominant in males and not in females ( 453 ) and nociception is regulated by spinal serotonin and noradrenaline in male but not in female mice ( 454 ). It has also recently been shown that ex vivo treatment of live human organ donor spinal cord tissue with BDNF downregulates markers of inhibition and upregulates markers of facilitated excitation in dorsal horn neurons from males but not females ( 455 ). Lastly, administration of IL-23 (Interleukin 23) produces mechanical allodynia in female but not male mice and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking IL-23 or its cognate receptor.…”