Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems

Abstract

Nociception and opioid antinociception in females are pliable processes, varying qualitatively and quantitatively over the reproductive cycle. Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR₁)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception. This provides a window into pharmacologically accessing intrinsic opioid analgesic/anti-allodynic systems. In diestrus, membrane estrogen receptor alpha (mERα) signals via mGluR₁ to suppress spinal endomorphin 2 (EM2) analgesia. Strikingly, in the absence of exogenous opioids, interfering with this suppression in a chronic pain model elicits opioid anti-allodynia, revealing contributions of endogenous opioid(s). In proestrus, robust spinal EM2 analgesia is manifest but this requires spinal dynorphin/KOR and glutamate-activated mGluR₁. Furthermore, spinal mGluR₁ blockade in a proestrus chronic pain animal (eliminating spinal EM2 analgesia) exacerbates mechanical allodynia, revealing tempering by endogenous opioid(s). A complex containing mu-opioid receptor, KOR, aromatase, mGluRs, and mERα are foundational to eliciting endogenous opioid anti-allodynia. Aromatase-mERα oligomers are also plentiful, in a central nervous system region-specific fashion. These can be independently regulated and allow estrogens to act intracellularly within the same signaling complex in which they are synthesized, explaining asynchronous relationships between circulating estrogens and central nervous system estrogen functionalities. Observations with EM2 highlight the translational relevance of extensively characterizing exogenous responsiveness to endogenous opioids and the neuronal circuits that mediate them along with the multiplicity of estrogenic systems that concomitantly function in phase and out-of-phase with the reproductive cycle.

Fig 1.

Analgesic responsiveness to spinal EM2 is governed by dynamic, pliable interactions among MOR, KOR, mGluR₁, mGluR_2/3, mERα and aromatase (Aro) within an oligomer that tracks the estrous cycle. In diestrus, E2 synthesized within the oligomer comprised of Aro-mERα-mGluR₁-MOR stimulates mGluR₁ via signaling by mERα to suppress analgesic responsiveness to intrathecal EM2 by inhibiting MOR signaling. Blockade of mERα/mGluR₁ or inhibition of Aro neutralizes MOR inhibition, unmasking endogenous MOR-mediated (EM2) analgesia. The disconnection of suppressive mERα-mGluR₁ signaling, the transition from mERα to glutamate (Glut) activation of mGluR₁, which now signals in partnership with mGluR_2/3, and augmented spinal Dyn/KOR signaling, which signals in collaboration with MOR in an oligomer of mGluR₁-mGluR_2/3-KOR-MOR that is different from that of diestrus, triggers the appearance of spinal EM2 analgesia. Inhibition of Glut release and thus a decrease in mGluR₁/mGluR_2/3 signaling activity eliminates the expression of endogenous spinal opioid analgesia, resulting in the worsening of allodynia in neuropathic pain rats. An organizational framework in which the spinal neurons coexpressing the pertinent signaling proteins (oligomerized therein) are in apposition to EM2-expressing, Dyn/Glut-containing varicosities likely underlies these observations. This organization would permit individual neurons to vary responsiveness to EM2 as a function of the ebb and flow of spinal Dyn and Glut signaling.