Sexually Dimorphic Recruitment of Spinal Opioid Analgesic Pathways by the Spinal Application of Morphine

Abstract

Current evidence for sex-based nociception and antinociception, largely confined to behavioral measures of pain sensitivity, chronic pain syndromes, and analgesic efficacy, provides little mechanistic insights into biological substrates causally associated with sexual dimorphic pain experience. Spinal cord has been shown to be a central nervous system region in which regulation of opioid antinociceptive substrates manifest sexual dimorphism. This site was therefore chosen to explore whether or not differential mechanisms underlie comparable spinal opioid antinociception in male and female rodents. Intrathecal (i.t.) application of morphine to male and female rats produces a thermal antinociception equivalent in magnitude and temporal profile. Nevertheless, it results from the sex-based differential recruitment of spinal analgesic components. As expected, the spinal -opioid receptor is critical for i.t. morphine antinociception in both sexes. However, in females, but not males, activation by i.t. morphine of spinal -opioid receptors is a prerequisite for spinal morphine antinociception. Furthermore, in females, but not males, i.t. application of antidynorphin antibodies substantially attenuates the antinociception produced by i.t. morphine. This indicates that the antinociception that results from the i.t. application of morphine in females requires the functional recruitment of spinal dynorphin. Female-specific recruitment by i.t. morphine of a spinal dynorphin/-opioid receptor pathway results from organizational consequences of ovarian sex steroids and not the absence of testicular hormones. These observations suggest that sexual dimorphic pain and analgesic mechanisms might be far more pervasive than commonly thought and underscore the imperative for including female as well as male subjects in all studies of pain and antinociception.Sexual dimorphism in nociception and opioid antinociception has been well documented in humans (Ellermeier and Westphal, 1995;Unruh, 1996;Berkley, 1997;Fillingim et al., 1998;Walker and Carmody, 1998) and laboratory animals (Mogil et al., 1993;Coyle et al., 1995Coyle et al., , 1996Kayser et al., 1996;Mogil and Chanda, 2005). Previously, evidence for sexbased nociception and antinociception has been largely confined to behavioral measures revealing differential pain sensitivity, frequency and severity of chronic pain syndromes, and divergent analgesic efficacy of opioid receptor-type-selective agonists. Although underscoring the occurrence of sexual dimorphism in pain processing and its regulation, these studies provide little insight into biological substrates and neuronal organizational parameters that might underlie such sexual dimorphism.The spinal cord has been shown to be a central nervous system region in which components of opioid analgesic pathways and their regulation manifest sexual dimorphism. For example, the density of the -opioid receptor (KOR) and its distribution within axon terminals differs between the spinal cord of male and female rodents (Harris et al....

Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats

“…Regarding sex, our results are similar to previous findings (LaPrairie and Murphy, 2007) being the thermal threshold significantly higher in neonatally injured females than males and controls. This has been supported by findings that ovarian sex hormones modulate dynorphin/kappa-opioid receptor pathway which is a prerequisite for spinal morphine antinociception (Liu et al, 2007).…”

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

“…This formulation is supported by (i) the femalespecific expression in spinal cord of heterodimeric MOR/KOR that parallels the manifestation of a dynorphin/KOR component of spinal morphine antinociception; (ii) the inability of either i.t. U50,488 or U69,593, both of which activate monomeric KOR, to produce antinociception by using the tail flick test during proestrous, during which time the same nociceptive test indicates a substantially augmented KOR component of spinal morphine antinociception; and (iii) the absence of a dynorphin/KOR component of spinal morphine antinociception in males (17) despite the presence in their spinal cord of monomeric KOR.…”

“…To demonstrate this attribute of dynorphin 1-17, we used i.t. morphine, shown previously by this laboratory to release endogenous dynorphin (17), which was then cross-linked in vitro and processed for KOR IP (Materials and Methods and SI Materials and Methods). Dynorphin or KOR Western blot analyses of the above immunoprecipitate also revealed a signal of ≈120 kDa (Fig.…”

“…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.…”

“…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.…”