Sex‐specific characteristics of cells expressing the cannabinoid 1 receptor in the dorsal horn of the lumbar spinal cord

Abstract

It is becoming increasingly clear that robust sex differences exist in the processing of acute and chronic pain in both rodents and humans. However, the underlying mechanism has not been well characterized. The dorsal horn of the lumbar spinal cord is the fundamental building block of ascending and descending pain pathways. It has been shown that numerous neurotransmitter and neuromodulator systems in the spinal cord, including the endocannabinoid system and its main receptor, the cannabinoid 1 receptor (CB 1 R), play vital roles in processing nociceptive information. Our previous findings have shown that CB 1 R mRNA is widely expressed in the brain in sex-dependent patterns. However, the sex-, lamina-, and cell-type-specific characteristics of CB 1 R expression in the spinal cord have not been fully described. In this study, the CB 1 R-iCre-EGFP mouse strain was generated to label and identify CB 1 R-positive (CB 1 R GFP ) cells. We reported no sex difference in CB 1 R expression in the lumbar dorsal horn of the spinal cord, but a dynamic distribution within superficial laminae II and III in female mice between estrus and nonestrus phases. Furthermore, the cell-type-specific CB 1 R expression pattern in the dorsal horn was similar in both sexes. Over 50% of CB 1 R GFP cells were GABAergic neurons, and approximately 25% were glycinergic and 20-30% were glutamatergic neurons. The CB 1 R-expressing cells also represented a subset of spinal projection neurons. Overall, our work indicates a highly consistent distribution pattern of CB 1 R GFP cells in the dorsal horn of lumbar spinal cord in males and females.

Lifespan changes in cannabinoid 1 receptor mRNA expression in the female C57BL/6J mouse brain

“…Previous research has mainly focused on CB 1 R functions in cortical regions although functions involving the conserved subcortical regions are currently arousing more interest for a more complete understanding of the endocannabinoid system in conserved behavior and function (Soria‐Gomez et al., 2015). Previous work from our group comparing female mice in estrus and nonestrus (X. Liu et al., 2020) found no statistically significant difference in the number of CB 1 R‐positive cells in most brain regions (X. Liu et al., 2020) and the lumbar spinal cord (Zhang et al., 2022), indicating that the estrous cycle may not contribute to the differences in the number of CB 1 R‐positive cells at different ages. Moreover, two groups in our study, the 4‐ and 86‐week groups, were either sexually immature or aged.…”

“…Liu et al, 2020) found no statistically significant difference in the number of CB 1 R-positive cells in most brain regions (X. Liu et al, 2020) and the lumbar spinal cord (Zhang et al, 2022), indicating that the estrous cycle may not contribute to the differences in the number of CB 1 R-positive cells at different ages. Moreover, two groups in our study, the 4-and 86-week groups, were either sexually immature or aged.…”

“…Studies from our group and many others have shown that there is sexual dimorphism in the expression and function of the eCB system (Huang & Woolley, 2012;X. Liu et al, 2020;Tabata, 2015;Zer-Aviv & Akirav, 2016;Zhang et al, 2022). In addition, CB 1 Rs and other molecules of eCB system components, for example, endocannabinoid metabolic enzymes, participate extensively in brain functions related to age.…”