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.