Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

Abstract

The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka estrogen synthase), metabotropic glutamate receptor 1 (mGluR1), and MOR. During diestrus, spinal mERs, activated by locally synthesized estrogens, act with mGluR1 to suppress spinal EM2/MOR antinociception. The emergence of robust spinal EM2 antinociception during proestrus results from the loss of mER-mGluR1 suppression, a consequence of altered interactions within the oligomer. The chemical pairing of aromatase with mERs within the oligomer containing MOR and mGluR1 allows estrogens to function as intracellular messengers whose synthesis and actions are confined to the same signaling oligomer. This form of estrogenic signaling, which we term “oligocrine,” enables discrete, highly compartmentalized estrogen/mER-mGluR1 signaling to regulate MOR-mediated antinociception induced by EM2. Finally, spinal neurons were observed not only to coexpress MOR, mERα, aromatase, and mGluR1 but also be apposed by EM2 varicosities. This suggests that modulation of spinal analgesic responsiveness to exogenous EM2 likely reflects changes in its endogenous analgesic activity. Analogous suppression of spinal EM2 antinociception in women (eg, around menses, comparable with diestrus in rats) as well as the (pathological) inability to transition out of that suppressed state at other menstrual cycle stages could underlie, at least in part, the much greater prevalence and severity of chronic pain in women than men.

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

“…Our findings reveal that compromised spinal estrogenic and mGluR 1 activity, which unleashes antinociceptive responsiveness to i.t. EM2 in intact diestrous rats 46,47 reduced spinal opioid antiallodynia in spinal nerve ligated rats during diestrous. Conversely, compromised mGluR 1 signaling, which minimizes i.t.…”

“…For spinal drug delivery, a permanent indwelling cannula was inserted into the lumbar spinal cord subarachnoid space as described previously. 46,47 Spinal cannula implantation was performed concomitant with SNL. In brief, animals were anesthetized as described above, and an 8.0 cm PE-10 catheter (Becton, Dickinson and Company, Franklin Lanes, NJ) was inserted through the atlantooccipital membrane into the spinal subarachnoid space.…”

“…1,29,38 I.t. doses of MPP (10 nmol), YM298198 (25 nmol), fadrozole (2.5 nmol) and naloxone (25 nmol) were based on previous studies 8,11,18,35,44,46,47,62 in order to maintain parallelism of intrathecal treatments used in the current report and its two antecedent studies. 46,47…”

“…Spinal neurons coexpressing MOR, mERα mGluR 1 , and aromatase (estrogen synthase) are apposed by EM2 varicosities. 47 This provides an anatomical basis for physiologic modulation of endogenous spinal EM2 analgesic responsiveness by mERα-mGluR 1 signaling. Additionally, spinal dynorphin-expressing neurons that coexpress mGluR 1 and ERα are apposed by terminals expressing vesicular glutamate transporters (glutamatergic terminals).…”

“…45 During diestrus, spinal EM2/MOR antinociception is suppressed by spinally synthesized estrogens via their stimulation of spinal membrane estrogen receptors (mERs) that signal via metabotropic glutamate receptor 1 (mGluR 1 ). 47 The striking emergence of robust spinal EM2 antinociception during proestrus requires not only the loss of mER-mGluR 1 suppression, but also the emergence of signaling not present during diestrus. This includes increased release of spinal dynorphin, activation of spinal kappa-opioid receptors (KOR), and a switch in the endogenous agonist of mGluR 1 from mERα in diestrus to glutamate in proestrus.…”