Estrous (menstrual) cycle and estrogens influence pain sensitivity and analgesic effectiveness of µ-opioid receptor (MOR)-selective opioids, e.g., our recent finding that the analgesia elicited in female rats by the intrathecal (i.t.) application of the endogenous MOR ligand endomorphin 2 (EM2) is dampened during diestrus
but robust and comparable to that of males during proestrus. Uncovering the molecular bases for clamped spinal EM2 analgesia will reveal novel molecular targets for drug interventions that disinhibit, and thus harness,
endogenous EM2 analgesia, lessening the use of prescription opioids, and thereby their abuse. The organizing
rubric generating Aims is that the phasic nature of spinal EM2 analgesia over the estrous cycle results from the
plasticity of interactions among spinal MOR, ¿-opioid receptor (KOR), aromatase (Aro), membrane estrogen
receptor a (mERa), mGluRs and their associated signaling partners. The first three aims focus on the molecular components (and their organization) that regulate i.t. EM2 analgesia. The fourth aim investigates translational relevance of findings. Aim 1 tests the hypothesis that during diestrus, spinal mERa-mGluR1 signaling,
via phospholipase C and ß-arrestin, dampens spinal EM2 analgesia. Aim 2 tests the hypothesis that during
proestrus, mERa and ß-arrestin are no longer relevant to spinal EM2 analgesia; mGluR1 now organizes with
mGluR2/3 to signal via c-Src, facilitating spinal dynorphin release, which enables robust spinal EM2 analgesia
to emerge. Aim 3 tests the hypothesis that spinal cord contains a novel modulatory oligomer comprised of
MOR, KOR, Aro (thus locally synthesized estrogens), mERa, mGluR1 and mGluR2/3 that subserves the dynamic modulation of spinal EM2 analgesia over the estrous cycle. Aim 3 also tests the hypothesis that variable activation of mERa (resulting from fluctuating spinal Aro activity, and thus the synthesis of estrogens immediately
proximal to mERa) drives reorganization of the predicted oligomer in diestrus vs. proestrus. Aim 4 tests the
hypothesis that interventions shown in Aim 1 to restore spinal EM2 analgesia (e.g., blockade of spinal mERa,
mGluR1, or phospholipase C) will be antinociceptive in diestrous rats undergoing chronic pain, which should
augment the endogenous spinal EM2 system. Conversely, Aim 4 will also test the hypothesis that interventions
shown in Aim 2 to eradicate spinal EM2 analgesia (e.g., blockade of spinal mGluR2/3, c-Src) will be pronociceptive in proestrous rats experiencing chronic pain. Collectively, proposed research will provide a new paradigm
and suggest new molecular targets (e.g., the predicted oligomer, spinal ERa/Aro) for developing novel pharmacotherapies for pain relief that harnesses the powerful endogenous EM2/MOR analgesic system. Therapies
that harness endogenous opioids would lessen the need for their exogenous counterparts, thereby circumventing prescription opioid abuse, which has reached epidemic proportions. Additionally, findings will provide insight into etiology of chronic pain in women, since dysfunction of the physiological switch from EM2 analgesically non-responsive to responsive states is likely to facilitate developing and/or sustaining chronic pain.
