Estrogen suppresses mu-opioid- and GABAB-mediated hyperpolarization of hypothalamic arcuate neurons

Abstract

The effects of estrogen on the response of hypothalamic arcuate neurons to mu-opioid and GABAB agonists were investigated. Intracellular recordings were made from arcuate neurons in slices prepared from ovariectomized guinea pigs that were pretreated with estrogen or vehicle. Estrogen shifted the dose-response curve to the mu-opioid agonist DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) by 3.4-fold; the EC50 for DAMGO was 240 +/- 25 nM in estrogen-treated females versus 70 +/- 12 nM in the controls. The maximal hyperpolarization induced by DAMGO was equivalent in neurons from both groups. The Ke for the naloxone antagonism of the DAMGO response was similar in both groups, which would indicate that the affinity of the mu-receptor was unchanged. To explore where in the receptor/G-protein/K+ channel cascade estrogen may be acting to attenuate the mu-opioid-mediated hyperpolarization, the response to the GABAB agonist baclofen was also tested. Estrogen treatment also shifted the dose-response curve for the baclofen-induced hyperpolarization by 3.3-fold without altering the maximum hyperpolarization; the EC50 shifted from 11.0 +/- 4.0 microM to 36.0 +/- 5.0 microM. All of the neurons were identified after linking the intracellular biocytin with streptavidin-FITC, and a subpopulation of cells in both groups were immunoreactive for beta-endorphin. We conclude that estrogen decreases the functional coupling of the mu- opioid and GABAB receptors to the inwardly rectifying K+ channel possibly through an action on the G-protein.

The potency of mu-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17 beta-estradiol

“…The mechanism of estrogenic modulation of opioidergic tone does not seem to involve changes in the affinity and/or number of hypothalamic Jo receptors (Zhang et al, 1993). Instead, we have previously shown that a 24 hr treatment of ovariectomized guinea pigs with estradiol benzoate in vivo leads to a threefold reduction in w-opioid potency compared with oil-treated controls (Kelly et al, 1992). In the present study, in vitro exposure of hypothalamic slices to E, was used to characterize further the time course and concentration dependence of this, or a similar, estrogenic effect.…”

“…Furthermore, our previous work has shown that a 24 hr exposure to estradiol results in a reduced DAMGO potency in all of the ARC neurons that were tested (Kelly et al, 1992). Thus, there may also be a time dependence to this regulation of endogenous opioids.…”

“…We have previously shown that the p-opioid and GABA, receptors are G-protein coupled to the same potassium conductance in ARC neurons (Loose et al,199 1). As with DAMGO, the potency of the GABA, agonist baclofen is decreased following exposure to E, for 24 hr (Kelly et al, 1992). Therefore, E,'s ability to alter the potency and/or efficacy of neurotransmitters is not limited to the cl-opioid system.…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…Both μ-opioid receptor (e.g., by β-endorphin or by selective μ-opioid agonists) or GABA B receptor activation of these GIRK channels directly hyperpolarize and thereby inhibit hypothalamic neurons (Loose et al, 1990, Kelly et al, 1992, Lagrange et al, 1994, Lagrange et al, 1995, Lagrange et al, 1996. Brief (<20 min) application of E2 or BSA-E2 in vitro causes a four-fold decrease in the potency of μ-opioid receptor agonists and GABA B receptor agonists to inhibit POMC neurons (Lagrange et al, 1994, Lagrange et al, 1996, indicating that a membrane ER (mER) is involved.…”

Sex Steroid–Opioid Interactions Associated with the Temporal Component of Avian Calling Patterns

“…Receptor protein regulation through the genomic action of steroids and the consequences on modulating neurotransmission are established at time scales beyond the phenotypical properties of neurons controlling the expression of stimulus driven behavior. However, as steroids can also modulate the acute effects of m-opioid agonists on potassium membrane conductance at the membrane level (Kelly et al, 1992), thereby influencing interspike intervals of action potentials by membrane hyperpolarization, a more causal involvement of receptor efficacy in regulating the ''shaping'' of behavior can be expected.…”