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 micro-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 kappa-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/kappa-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.