Estrogen facilitates and the kappa and mu opioid receptors mediate antinociception produced by intrathecal (−)-pentazocine in female rats

Abstract

Pentazocine, a mixed-action kappa opioid receptor (KOR) agonist, has high affinity for both KOR and the mu opioid receptor (MOR), and has been shown clinically to alleviate pain with a pronounced effect in women. However, whether local application of pentazocine in the spinal cord produces antinociception and the contribution of spinal KOR and MOR in mediating the effect of pentazocine in female rats remain unknown. Also, it is not known whether pentazocine-induced antinociception in females is estrogen-dependent. Hence, we investigated whether intrathecal (i.t.) (−)-pentazocine produces thermal antinociception and whether estrogen modulates the drug effect in female rats. Only the highest dose of pentazocine (500 nmol) was effective in producing antinociception in ovariectomized (OVX) rats. In contrast, pentazocine produced antinociception in estradiol-treated ovariectomized females (OVX+E) rats with the lowest effective dose being 250 nmol. KOR or MOR mediated the effect of the lowest effective dose in OVX+E rats; however, MOR blockade extended the KOR-mediated effect of 500 nmol pentazocine in both groups. In normally cycling females, the 250 nmol dose was effective in producing antinociception at the proestrous, but not at the diestrous stage of the estrous cycle. Thus, estrogen facilitates and KOR or MOR mediate the antinociceptive effect of i.t. (−)-pentazocine in female rats. Selective doses of (−)-pentazocine, with or without MOR blockade, may have a therapeutic benefit.

Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn

“…Considering that LS represents a silent state of pain vulnerability, we speculate that failure of KOR signaling could determine the greater predisposition of females to develop persistent postsurgical pain. Further studies are needed to determine the contribution of hormonal (Lawson et al, 2010;Robinson et al, 2016;Sternberg et al, 2004), neurochemical, and genetic (Fillingim and Gear, 2004;Mogil et al, 2003;Rasakham and Liu-Chen, 2011)…”

“…Numerous studies report sex differences in the ability of exogenous KOR ligands to modulate pain in both rodents (Auh and Ro, 2012;Lomas et al, 2007;Mogil et al, Robinson et al, 2016;Sternberg et al, 2004;Terner et al, 2003a) and humans (Gear et al, 1996a;Gear et al, 1996bGear et al, , 1999Pande et al, 1996b). However, questions of sex differences in endogenous opioid receptor analgesia have not been rigorously studied.…”

Expression of aromatase in the rostral ventromedial medulla and its role in the regulation of visceral pain

“…In the RVM, morphine and endogenous opioid peptides produce analgesia primarily via activating the μ‐type opioid receptor (MOR) and phosphorylation of MOR (pMOR) has been implicated in morphine tolerance, that is, decrease in MOR‐mediated analgesia. As previous studies suggested that estrogens may affect MOR signaling, we therefore explored whether aromatase inhibitors abrogated CPM‐induced colorectal hyperalgesia via affecting MOR phosphorylation. Figure A compares the relative level of pMOR in the RVM in saline‐treated, CPM‐treated, CPM + vehicle and CPM + FAD groups.…”

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

“…GPER (GPR30) co-localise with other pharmacologic classes of G α protein ligands, modulating serotonin and neuronal acetylcholine receptors (Xu et al 2009;Hammond et al 2011). Estrogen also modulates the strength of antinociception provided by opioid receptor agonists (Robinson et al 2016). The estrogen templates 6b, 6f, 6g, 6h and 6j use fitting points common to ligands acting at acetylcholine, serotonin and opiate receptors (Williams 2018).…”