Gender difference in analgesic response to the kappa-opioid pentazocine

Gear, Robert W.; Gordon, Newton C.; Heller, Philip H.; Paul, Steven M.; Miaskowski, Christine; Levine, Jon D.

doi:10.1016/0304-3940(96)12402-2

Cited by 212 publications

(118 citation statements)

References 12 publications

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“…42). Gear and colleagues (10)(11)(12)(13), in contrast, have reported that women are more sensitive to the inhibition of molar extraction pain by a number of nonselective -opioid analgesics including pentazocine. We observed a trend in the opposite direction presently: toward greater analgesia in nonredheaded men than women.…”

Section: Discussionmentioning

confidence: 99%

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Mogil

Wilson

Chesler

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

470

317

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Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from -opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates -opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered -opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the -opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

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Section: Discussionmentioning

confidence: 99%

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Mogil

Wilson

Chesler

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

470

317

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“…Females have greater antinociception responsiveness to KOR ligands than do males (11)(12)(13)(14)32), but compelling mechanistic formulations have not undergirded these observations. Dimeric MOR/KOR represents a female-specific signaling molecule that could underlie reports of enhanced KOR antinociception in women vs. men.…”

Section: Discussionmentioning

confidence: 99%

“…For example, there is little mechanistic understanding of why women are more likely than men to experience myriad chronic pain syndromes (1-3) as well as recurrent pain, more severe levels of pain, and pain of longer duration (10). Similarly, reports of more robust κ-opioid receptor (KOR) antinociception in females vs. males (11)(12)(13)(14) are not accompanied by compelling mechanistic rationales.In addition to proposed genetic contributions (15), the milieu of ovarian sex steroids is thought to contribute to sex-dependent nociception (5, 6) and opioid antinociception (5, 16). However, sex steroid molecular targets and their altered functionality that are relevant to sex-dependent nociception and opioid antinociception are not defined.…”

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confidence: 99%

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confidence: 99%

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Formation of μ-/κ-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia

Chakrabarti

Liu²,

Gintzler³

2010

Proc. Natl. Acad. Sci. U.S.A.

120

137

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Sexually dimorphic nociception and opioid antinociception is very pervasive but poorly understood. We had demonstrated that spinal morphine antinociception in females, but not males, requires the concomitant activation of spinal μ-and κ-opioid receptors (MOR and KOR, respectively). This finding suggests an interrelationship between MOR and KOR in females that is not manifest in males. Here, we show that expression of a MOR/KOR heterodimer is vastly more prevalent in the spinal cord of proestrous vs. diestrous females and vs. males. Cross-linking experiments in combination with in vivo pharmacological analyses indicate that heterodimeric MOR/KOR utilizes spinal dynorphin 1-17 as a substrate and is likely to be the molecular transducer for the female-specific KOR component of spinal morphine antinociception. The activation of KOR within the heterodimeric MOR/KOR provides a mechanism for recruiting spinal KOR-mediated antinociception without activating the concomitant pronociceptive functions that monomeric KOR also subserves. Spinal cord MOR/KOR heterodimers represent a unique pharmacological target for female-specific pain control.estrous cycle | sexual dimorphism | sex steroids | signaling complexes | estrogen and progesterone S exual dimorphism in nociception and opioid antinociception has been extensively documented in humans (1-4) and laboratory animals (5-9). Nevertheless, underlying molecular mechanisms causally associated with sex-dependent nociception and opioid antinociception remain enigmatic. For example, there is little mechanistic understanding of why women are more likely than men to experience myriad chronic pain syndromes (1-3) as well as recurrent pain, more severe levels of pain, and pain of longer duration (10). Similarly, reports of more robust κ-opioid receptor (KOR) antinociception in females vs. males (11)(12)(13)(14) are not accompanied by compelling mechanistic rationales.In addition to proposed genetic contributions (15), the milieu of ovarian sex steroids is thought to contribute to sex-dependent nociception (5, 6) and opioid antinociception (5, 16). However, sex steroid molecular targets and their altered functionality that are relevant to sex-dependent nociception and opioid antinociception are not defined. This laboratory reported (17) that the antinociception produced by intrathecal (i.t.) morphine results from the sex-based differential recruitment of spinal analgesic components. In males, spinal morphine antinociception results from the exclusive activation of spinal μ-opioid receptor (MOR). In contrast, in females, spinal morphine antinociception requires the concomitant activation of spinal MOR and KOR (17). The most parsimonious explanation for this sex-dependent dichotomy would be the female-specific recruitment of spinal MOR/KOR heterodimers.We investigated the hypothesized sexually dimorphic expression in spinal cord of MOR/KOR heterodimers by comparing their presence in the spinal cord of male, proestrous and diestrous rats as well as rats subjected to ovariectomy. Here, ...

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“…In humans, the mu agonist morphine (Sarton et al, 2000) and the mixed-action opioids pentazocine, butorphanol and nalbuphine (Gear et al, 1996a(Gear et al, ,b, 1999(Gear et al, , 2000 produced greater or more prolonged analgesia in women than in men. Sex differences in opioid antinociception also are widely reported in rodents, although they tend to be in the opposite direction to those observed in humans.…”

Section: Introductionmentioning

confidence: 99%

Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats

Stoffel

Ulibarri

Craft

2003

Pain

168

137

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The purpose of this study was to examine how gonadal steroid hormones modulate basal nociception and morphine antinociception relative to regulating reproduction in the adult rat. Male and female Sprague-Dawley rats were either gonadectomized (GDX) or sham-gonadectomized (sham); GDX males were implanted subcutaneously with capsules containing testosterone (T), estradiol (E2), dihydrotestosterone (DHT), E2 and DHT, or nothing (0). GDX females received E2, T, or empty (0) capsules immediately after surgery, and vehicle or progesterone (P4) injections at 4-day intervals. Basal nociception and morphine antinociception were tested 28 days after surgery on 50°C and 54°C hotplate tests, and reproductive behavior and physiology were assessed shortly thereafter. There were no significant differences in baseline hotplate latencies among the male treatment groups, but morphine was significantly more potent in sham and GDX + T males than in GDX + 0 males. The ability of T to increase morphine's potency was approximated by its major metabolites E2 and DHT, given together but not alone. Baseline hotplate latencies were higher in sham females tested during diestrus than in those tested during estrus. Morphine was significantly more potent in sham females tested during proestrus and diestrus than in those tested during estrus. Baseline hotplate latencies were significantly higher, and morphine was significantly less potent in GDX + E2, GDX + E2/P4 and GDX + T females than in GDX + 0 females. All group differences in basal nociception and morphine antinociception observed on the 50°C hotplate test were smaller and generally nonsignificant on the 54°C hotplate test. Steroid manipulations produced the expected changes in reproductive behaviors and steroid-sensitive organs. These results demonstrate that in adult rats, gonadal steroid manipulations that are physiologically relevant, modulate (1) basal nociception in females but not males, and (2) morphine's antinociceptive potency in both males and females.

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Gender difference in analgesic response to the kappa-opioid pentazocine

Cited by 212 publications

References 12 publications

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Formation of μ-/κ-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia

Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats

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