Sex Differences in the Amygdaloid Projections to the Periaqueductal Gray During Inflammatory Pain in the Rat

Abstract

The central nervous system is involved in modulation of pain and is sexually dimorphic in neural organization and function. Sex hormones are implicated in pain modulation and studies suggest that estradiol increases pain and decreases analgesia. Previous studies have identified that sex differences in descending modulation contribute to dimorphic pain and analgesia. The midbrain periaqueductal gray (PAG) is a critical brain region for descending inhibition of pain. The PAG projects to the rostral ventromedial medulla (RVM), which projects to the spinal cord to inhibit pain signals. In addition to pain, this descending system can be activated by endogenous (e.g. endorphins) and/or exogenous (e.g. morphine) substances and sex differences have been reported in the activation of this system during pain and analgesia. Forebrain structures, such as the amygdala, project to and engage the PAG descending circuit, however studies examining forebrain projections to the PAG have been conducted exclusively in males. Further, the central nucleus of the amygdala (CeA) seems to be involved in pain facilitation, while the medial nucleus (MeA) is involved in pain inhibition. The objective of the present study was to delineate the neural projections from the amygdala to the PAG in the female rat and determine if they are (1) sexually dimorphic in anatomical organization, (2) estradiol‐sensitive, and (3) activated by inflammatory pain. The retrograde tracer fluorogold (FG) was injected into the ventrolateral PAG of adult male (n=4) and female (n=4) Sprague Dawley rats. After 10 days, complete Freund's adjuvant (CFA) was injected into the right hind paw to induce inflammatory pain. Twenty‐four hours later, rats were perfusion fixed, brains were sectioned at 25 μm, then processed by immunohistochemistry. Fluorogold was visualized using diaminobenzidine (DAB) oxidation and Fos or estrogen receptor (ERα)was visualized using DAB oxidation in the presence of nickel. Heavy projections from the CeA and MeA to the PAG were observed in females, with a greater number of MeA neurons projecting to the PAG in females than the CeA. Overall, inflammatory pain induced greater Fos expression in the CeA and MeA of males. Interestingly, females had greater Fos expression in CeA‐PAG projection neurons, while in males Fos expression was greater in MeA‐PAG neurons. ERα expression was comparable between the sexes in the CeA, and higher in MeA neurons in females. Together our data indicate that although the MeA‐PAG projection is denser in females, inflammatory pain activates this pathway to a greater degree in males. This suggests that descending inhibition is more ‘engaged’ in males during inflammatory pain. On the other hand, inflammatory pain results in a greater activation of the CeA‐PAG pathway in females, suggesting a pain faciliatory mechanism in females. We are currently using confocal microscopy to determine potential sex differences in the neurochemistry of this system that underlies dimorphic modulation of the PAG during pain.Support or Funding InformationThis research was supported by NIH grants DA16272 and AR49555 to AZM and the STC Program of NSF IBN‐9876754. This work was funded, in part, by a TWU Quality Enhancement Program grant awarded to DJC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.