Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

Abstract

The midbrain periaqueductal gray (PAG), and its descending projections to the rostral ventromedial medulla (RVM), provides an essential neural circuit for opioid-produced antinociception. Recent anatomical studies have reported that the projections from the PAG to the RVM are sexually dimorphic and that systemic administration of morphine significantly suppresses pain-induced activation of the PAG in male but not female rats. Given that morphine antinociception is produced in part by disinhibition of PAG output neurons, it is hypothesized that a differential activation of PAG output neurons mediates the sexually dimorphic actions of morphine. The present study examined systemic morphine-induced activation of PAG-RVM neurons in the absence of pain. The retrograde tracer fluorogold (FG) was injected into the RVM to label PAG-RVM output neurons. Activation of PAG neurons was determined by quantifying the number of Fos-positive neurons one hour following systemic morphine administration (4.5 mg/kg). Morphine produced comparable activation of the PAG in both male and female rats, with no significant differences in either the quantitative or qualitative distribution of Fos. While microinjection of FG into the RVM labeled significantly more PAG output neurons in female rats than male rats, very few of these neurons (20%) were activated by systemic morphine administration in comparison to males (50%). The absolute number of PAG-RVM neurons activated by morphine was also greater in males. These data demonstrate widespread disinhibition of PAG neurons following morphine administration. The greater morphine-induced activation of PAG output neurons in male compared to female rats is consistent with the greater morphine-induced antinociception observed in males. Keywordspain; morphine analgesia; pain inhibition; opioid; sexual dimorphism endogenous descending pathway Morphine and other mu-opioid receptor agonists are the most effective pharmacological treatment for the alleviation of persistent pain. However, it is becoming increasingly clear that morphine does not produce the same degree of analgesia in males and females. In the majority of studies reported to date, morphine produced a greater antinociceptive response in males in Correspondence to: Anne Z. Murphy, Ph.D., Dept. Biology, Center for Behavioral Neuroscience, Georgia State University, PO Box 4010, Atlanta, amurphy@gsu.edu, Phone: 404.463.9661, Fax: 404.651.2509 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Bodnar et al., 1988,Craft, 2003b,Craft, 2003a,Cook and Nickerson, 2005,Wang et al., 2006. Sex difference...

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