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

Abstract

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, ...

Mu Opioids and Their Receptors: Evolution of a Concept

“…7), including methadone, heroin, fentanyl, and morphine-6b-glucuronide Chang et al, 1998;Pasternak, 2004Pasternak, , 2010. Additional studies have explored the roles of genetic backgrounds and sex issues in more detail (Kepler et al, 1991;Gear et al, 1999;Kest et al, 1999;Lariviere et al, 2002;Wilson et al, 2003a,b;Gintzler et al, 2008;Chakrabarti et al, 2010;Mogil and Bailey, 2010). Thus, these preclinical studies suggest a genetic basis for differing sensitivities of individuals to each opiate and to different relative potencies of mu opiates from patient to patient.…”

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

“…The distinction between the latter two types can be considered the difference between 'quantitative' and 'qualitative' sex differences. Although attention has mostly been paid to documenting quantitative sex differences in pain, a growing number of examples of qualitative differences in pain have been reported 31,39,43,[53][54][55][56][57][58][59][60][61][62][63][64] , and these promise to be far more important in the long run. As a practical matter, analgesics are routinely titrated according to their effect, which will effectively mitigate any sex differences along with other sources of inter-individual variability.…”

“…Although most of the research has been carried out in mice, for κ-opioid analgesia this sex difference is seen in humans as well, with genetic dysfunction of MC1R leading to increased pentazocine analgesia in women but not men 39 . Studies have documented that the neural circuitry subserving analgesia from sex steroids and morphine in the rat spinal cord show profound sex divergence 60,61,92 , and recent work suggests that the core of the sex difference stems from a bias in μ-and/or κ-opioid heterodimer expression 59,93 . These heterodimers -the formation of which is under regulation by spinal oestrogen synthesis 93 -are vastly more prevalent in the female rat spinal cord than in the male spinal cord and are activated by endogenous dynorphin 1-17, which itself can be released by intrathecal injection of morphine, producing effects that are not seen in monomeric κ-opioid Box 2 | Are there sex differences in laboratory pain sensitivity?…”

“…receptors 59 . These results may explain the known dependency of morphine analgesia in female (but not male) mice on the κ-opioid receptor gene 41 .…”

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…A number of opioid receptor heteromers has been described during the last few years for instance δ opioid receptor (DOR)-κ opioid receptor(KOR) heteromers [31], DOR-µ opioid receptor (MOR) heteromers [32] [33] and MOR-KOR heteromer [34] but also heteromers with other receptor types e.g. an α 2A adrenergic-MOR heteromer [28] [29] [35]- [37] guiding future research also to bivalent ligands which could give additional functional informations but also new therapeutic approaches.…”