Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

Abstract

Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to -opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.

Pleiotropic Opioid Regulation of Spinal Endomorphin 2 Release and Its Adaptations to Opioid Withdrawal Are Sexually Dimorphic

“…The male-specific enhanced utilization of the spinal EM2/ MOR-coupled system during opioid withdrawal is consistent with other reports of MOR-related sexual dimorphism, e.g., 1) greater antinociceptive responsiveness to morphine of male versus female rats (Cicero et al, 1996(Cicero et al, , 1997Wang et al, 2006;Loyd et al, 2008), 2) greater K ϩ -induced release of EM2 from spinal cord of male versus female rats (Gupta et al, 2007), 3) exclusive mediation of spinal morphine antinociception by spinal MOR in males but KOR as well as MOR in females (Liu et al, 2007), and 4) the almost 5-fold greater expression of MOR heterodimerized with KOR in the spinal cord of females than males (Chakrabarti et al, 2010). All suggest the predominance and perhaps the exclusivity of MOR-mediated events in males versus the importance in females of alternative opioid systems, alone or in combination with MOR.…”

Sex Difference in κ-Opioid Receptor (KOPR)-Mediated Behaviors, Brain Region KOPR Level and KOPR-Mediated Guanosine 5′-O-(3-[35S]Thiotriphosphate) Binding in the Guinea Pig

“…In addition, other systems involved in pain modulation have sex differences. For example, male rats have a higher level of MOPR in the ventrolateral PAG compared with cycling females (Loyd et al, 2008). The higher levels of MOPR and KOPR in the PAG suggest higher endogenous opioid tone in males.…”

Activation of μ-Opioid Receptors in the Dorsal Striatum is Necessary for Adult Social Attachment in Monogamous Prairie Voles

“…Brains from six male and six female prairie voles were collected and prepared for MOR autoradiography using H(N)]-DAMGO ([3H]DAMGO) (PerkinElmer, MA) and analyzed as described previously (Loyd et al, 2008). Noncompetitive binding to brain slices was measured using [3H]DAMGO alone.…”