Spinal Endomorphin 2 Antinociception and the Mechanisms That Produce It Are Both Sex- and Stage of Estrus Cycle–Dependent in Rats

Abstract

Endomorphin 2 (EM2) is the predominant endogenous mu-opioid receptor (MOR) ligand in the spinal cord. Given its endogenous presence, antinociceptive responsiveness to the intrathecal application of EM2 most likely reflects its ability to modulate nociception when released in situ. In order to explore the physiological pliability of sex-dependent differences in spinal MOR-mediated antinociception, we investigated the antinociception produced by intrathecal EM2 in male, proestrus female, and diestrus female rats. Antinociception was reflected by changes in tail flick latency to radiant heat. In females, the spinal EM2 antinociceptive system oscillated between analgesically active and inactive states. During diestrus, when circulating estrogens are low, spinal EM2 antinociceptive responsiveness was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal EM2 antinociception was robust and comparable in magnitude to that manifest by males. Furthermore, in proestrus females, spinal EM2 antinociception required spinal dynorphin and kappaopioid receptor activation, concomitant with MOR activation. This is required for neither spinal EM2 antinociception in males nor the antinociception elicited in proestrus females by spinal sufentanil or [d-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin, which are prototypic MOR-selective nonpeptide and peptide agonists, respectively. These results reveal that spinal EM2 antinociception and the signaling mechanisms used to produce it fundamentally differ in males and females. Perspective The inability to mount spinal EM2 antinociception during defined stages of the estrus (and presumably menstrual) cycle and impaired transition from spinal EM2 analgesically nonresponsive to responsive physiological states could be causally associated with the well-documented greater severity and frequency of chronic intractable pain syndromes in women vs men.

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

“…Our laboratory recently demonstrated that spinal EM2 antinociception is not only greater in male rats than diestrous female rats, but also greater in proestrous than diestrous females [45]. We therefore hypothesized that regulation of spinal EM2 release is also sex and cycle dependent.…”

Morphine Analgesia Modification in Normotensive and Hypertensive Female Rats after Repeated Fluoxetine Administration

“…It has been shown that morphine activates serotoninergic dorsal raphe nucleus neurons. Microdialysis of this opioid into rat forebrain increases serotonin release in the nucleus accumbens, frontal cortex, amygdaloid nucleus, dorsal striatum, thalamus, hypothalamus and hippocampus [12].In 1989, investigations performed on female rats allowed for concluding that endogenous androgens and oestrogens could play a significant role in morphine efficacy in the visceral pain model [13].It has been proven in females that antinociceptive activity of endomorphin 2 located in the spinal cord ranged between analgesically active and inactive states [14]. When circulating oestrogens are low during dioestrus, female rats demonstrate increased sensitivity to pain.…”

“…The antinociception properties of spinal endomorphin 2 could be modulated by changes in concentration of sex hormone. It depends on both the rat's sex and the stage of the oestrus cycle [14].Noteworthy is the occurrence of sexual dimorphisms in neuron counts in the periaqueductal grey-rostral ventromedial medullary pathway (PAG-RVD) [15] and for the occurrence of opioid receptor expressions within the periaqueductal grey (PAG) [16]. Opioid receptor expression is probably lower in…”

“…It has been proven in females that antinociceptive activity of endomorphin 2 located in the spinal cord ranged between analgesically active and inactive states [14]. When circulating oestrogens are low during dioestrus, female rats demonstrate increased sensitivity to pain.…”

“…The antinociception properties of spinal endomorphin 2 could be modulated by changes in concentration of sex hormone. It depends on both the rat's sex and the stage of the oestrus cycle [14].…”