Pharmacological Modulation of Endogenous Opioid Activity to Attenuate Neuropathic Pain in Rats

We showed previously that spinal metabotropic glutamate receptor 1 (mGluR₁) signaling suppresses or facilitates (depending on the stage of estrous cycle) analgesic responsiveness to intrathecal endomorphin 2, a highly mu-opioid receptor-selective endogenous opioid. Spinal endomorphin 2 antinociception is suppressed during diestrus by mGluR₁ when it is activated by membrane estrogen receptor alpha (mERα) and is facilitated during proestrus when mGluR₁ is activated by glutamate. In the current study, we tested the hypothesis that in female rats subjected to spinal nerve ligation (SNL), the inhibition of spinal estrogen synthesis or blockade of spinal mERα/mGluR₁ would be antiallodynic during diestrus, whereas during proestrus, mGluR₁ blockade would worsen the mechanical allodynia. As postulated, following SNL, aromatase inhibition or mERα/mGluR₁ blockade during diestrus markedly lessened the mechanical allodynia. This was observed only on the paw ipsilateral to SNL and was eliminated by naloxone, implicating endogenous opioid mediation. In contrast, during proestrus, mGluR₁ blockade worsened the SNL-induced mechanical allodynia of the ipsilateral paw. Findings suggest menstrual cycle stage-specific drug targets for and the putative clinical utility of harnessing endogenous opioids for chronic pain management in women, as well as the value of, if not the necessity for, considering menstrual cycle stage in clinical trials thereof. PERSPECTIVE: Intrathecal treatments that enhance spinal endomorphin 2 analgesic responsiveness under basal conditions lessen mechanical allodynia in a chronic pain model. Findings provide a foundation for developing drugs that harness endogenous opioid antinociception for chronic pain relief, lessening the need for exogenous opioids and thus prescription opioid abuse.