The potency of mu-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17 beta-estradiol.
The mu-opioid agonist DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) hyperpolarizes the majority of arcuate hypothalamic (ARC) neurons by opening an inwardly rectifying potassium conductance. The EC50 for the DAMGO-induced hyperpolarization was 60 +/- 3 nM in ARC neurons from ovariectomized guinea pigs. Superfusion of 17 beta-estradiol (E2; 100 nM) for 20 min in vitro resulted in a significant decrease in DAMGO potency (EC50 = 212 +/- 16 nM) in 40% of the neurons that were tested. This rapid effect of E2 on the mu-opioid response was not mimicked by the biologically inactive isomer 17 alpha-estradiol. Multiple concentrations of E2 were used to generate an E2 concentration-response curve, with an EC50 of 9 nM and a maximal increase in the DAMGO EX50 of 411% of controls. The membrane properties and firing rate of E2-sensitive and E2-insensitive neurons were not different. Streptavidin-FITC labeling did not reveal any significant morphological differences between the groups, but a higher number of E2-sensitive cells was found in the lateral ARC and cell-poor zone. Moreover, immunocytochemical staining of the recorded cells revealed that beta-endorphin neurons were among those sensitive to E2. Therefore, E2 could increase beta-endorphin release by decreasing the potency of beta-endorphinergic autoinhibition, thus increasing the tonic opioid inhibition of E2-insensitive cells. Furthermore, the diffuse projections of hypothalamic beta-endorphin neurons would allow E2 to alter processes throughout the brain, as well as having local effects in the hypothalamus.
Lagrange
A H
AH
Department of Physiology, Oregon Health Sciences University, Portland 97201-3098.
Ronnekleiv
O K
OK
Kelly
M J
MJ
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009294:Narcotics / Q000819:agonists*; D009474:Neurons / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D004745:Enkephalins; D009294:Narcotics; D015221:Potassium Channels; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004958:Estradiol; D019204:GTP-Binding Proteins