Sex, Pain, and Opioids: Interdependent Influences of Sex and Pain Modality on Dynorphin-Mediated Antinociception in Rats

Abstract

The role of dynorphin A (1-17; Dyn) and its associated kappa opioid receptor (KOR) in nociception represents a longstanding scientific conundrum: Dyn and KOR (Dyn/KOR) have variously been reported to inhibit, facilitate, or have no effect on pain. We investigated whether interactions between sex and pain type (which are usually ignored) influenced Dyn/ KOR-mediated antinociception. Blockade of the spinal a 2 -noradrenergic receptor (a 2 -NAR) using yohimbine elicited comparable spinal Dyn release in females and males. Nevertheless, the yohimbine-induced antinociception exhibited sexual dimorphism that depended on the pain test used: in the intraperitoneal acetic acid-induced writhing test, yohimbine produced antinociception only in females, whereas in the intraplantar formalin-induced paw flinch test, antinociception was observed only in males. In females and males, both intrathecal Dyn antibodies and spinal KOR blockade eliminated the yohimbine-induced antinociception, indicating that Dyn/ KOR mediated it. However, despite the conditional nature of spinal Dyn/KOR-mediated yohimbine antinociception, both intraplantar formalin and intraperitoneal acetic acid activated spinal Dyn neurons that expressed a 2 -NARs. Moreover, Dyn terminals apposed KOR-expressing spinal nociceptive neurons in both sexes. This similar organization suggests that the sexually dimorphic interdependent effects of sex and pain type may result from the presence of nonfunctional (silent) KORs on nociceptive spinal neurons that are responsive to intraplantar formalin (in females) versus intraperitoneal acetic acid (in males). Our findings that spinal Dyn/KORmediated antinociception depends on interactions between sex and pain type underscore the importance of using both sexes and multiple pain models when investigating Dyn/KOR antinociception.

Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models

“…As dynorphin A has variously been reported to inhibit [49, 50] or facilitate pain [51, 52], the effect of dynorphin A on nociception was tested in our conditions. Three groups of neuropathic rats received intrathecal injection of saline (10 μL) and two non-paralytic doses (1 and 10 μg) of the synthetic dynorphin A. Intrathecal administration of dynorphin A(1–17) dose-dependently suppressed mechanical allodynia in ipsilateral paws, with the peak effect (48.8 and 60.5 % MPE) at 1 h and a duration of 4 h ( P  < 0.05, by two-way ANOVA followed by the post hoc Student–Newman–Keuls tests) (Fig.…”

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

“…The relationship between sex/estrous stage and nociception is exceedingly complex, varying with species/strain, nature of the painful stimulus, location of pain, method of measurement, and the interactions among these variables [16, 82]. In rats, sensitivity to colorectal distension is higher in proestrus than diestrus [83], but sensitivity to ureteral pain is higher in diestrus than proestrus [84].…”

The neuroanatomy of sexual dimorphism in opioid analgesia

“…The spinal cord dorsal horn contains high levels of estrogen receptors (both ERα and ERβ; [62, 81]), and there is evidence that these receptors interact with both MOR and KOR at the level of the spinal cord to alter antinociception [41, 61]. Kappa opioid receptors form heterodimers with MOR (KOR/MOR) in the spinal cord [17], and the levels of KOR/MOR are approximately 4-fold greater in the spinal cord of proestrus female versus male rats.…”