Neuronal and glial factors contributing to sex differences in opioid modulation of pain

Abstract

Morphine remains one of the most widely prescribed opioids for alleviation of persistent and/or severe pain; however, multiple preclinical and clinical studies report that morphine is less efficacious in females compared to males. Morphine primarily binds to the mu opioid receptor, a prototypical G-protein coupled receptor densely localized in the midbrain periaqueductal gray. Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray, and its descending projections to the rostral ventromedial medulla and spinal cord, as an essential descending inhibitory circuit mediating opioid-based analgesia. Remarkably, the majority of studies published over the following 30 years were conducted in males with the implicit assumption that the anatomical and physiological characteristics of this descending inhibitory circuit were comparable in females; not surprisingly, this is not the case. Several factors have since been identified as contributing to the dimorphic effects of opioids, including sex differences in the neuroanatomical and neurophysiological characteristics of the descending inhibitory circuit and its modulation by gonadal steroids. Recent data also implicate sex differences in opioid metabolism and neuroimmune signaling as additional contributing factors. Here we cohesively present these lines of evidence demonstrating a neural basis for sex differences in opioid modulation of pain, with a focus on the PAG as a sexually dimorphic core of descending opioid-induced inhibition and argue for the development of sex-specific pain therapeutics.

Signatures of sex: Sex differences in gene expression in the vertebrate brain

“…Besides the reproductive organs, most sex differences in the body are quantitative, in which the distribution differs between the two sexes but largely overlaps, as is the case with height or brain volume (Maney, 2016;Ritchie et al, 2018), as well as many physiological traits such as stress (Bangasser & Wicks, 2017), opioid sensitivity (Averitt, Eidson, Doyle, & Murphy, 2019), and immune response (Klein & Flanagan, 2016). What can manifest as a sex difference in a specific behavior, neural response, or gene expression may in fact originate from underlying differences in physiology.…”

Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation and neuro-immunity

“…We used DRG-enriched genes from Ray et al [4] and our DE gene sets to identify putative PINs. The largest connected components from PINs generated using the StringDB database [16] show multiple DRG-enriched and sex-differentially expressed genes known to be expressed in the glia (DUSP15, PRX, EGR2, DHH, FOXD3, ARTN), and involved in pain and inflammation, which points to a potential role for glia in sex differential pain processing in human peripheral nerves (shown in preclinical models [17]). Additionally, the presence of several neuronally expressed genes in the interaction network among the set of DRG-enriched genes (GFRA3, NTRK1, NGFR, RET and PPM1J) also suggests sex-differential glia-neuron crosstalk, which in turn can affect neuronal plasticity and excitability differently between the sexes.…”

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

“…As far as the analgesic therapy is concerned, the response is different in males and females, since men are more sensitive to the use of non-steroidal anti-inflammatory drugs, while morphine shows greater efficacy in women [285]. Several major factors can explain sex-differences in the modulation of pain with opioids, such as the neuro-anatomical organization and the neuro-physiological characteristics of the descending inhibitory circuit, whilst no sex-difference is known in the plasma concentration of morphine and/or its metabolites [286]. A series of studies carried out on post-operative pain revealed that male patients consumed morphine doses 2.4-times higher than women, confirming that women are more sensitive than men to morphine [287].…”