Evidence for Noradrenergic Mediation of Opioid Effects on Luteinizing Hormone Secretion

Ovariectomized rats received estradiol benzoate (EB; 7.5 μg/rat, on day 0 at 1000 h) and progesterone (P; 5 mg/rat, on day 2 at 1000 h). On day 2, these EB- and P-treated (EBP) rats received either saline (control; at 1215 and 1230 h), morphine sulfate (M; 45 μg/kg, at 1230 h), or naloxone (NAL; 2 μg/kg, at 1215 h), followed by M (at 1230 h), and were killed between 1445–1515 h. M treatment alone blocked the P-induced afternoon increases in serum LH and the medial basal hypothalamic LHRH levels, whereas NAL pretreatment counteracted the M-induced LH suppression. The involvement of central adrenergic systems in the M- and NAL-induced serum LH responses in EBP-treated and young male rats was next evaluated. In these rats, NAL injection elicited rapid increases in serum LH levels, which were blocked by M pretreatment. The dopamine agonist, apomorphine, or antagonist, pimozide, failed to inhibit LH release induced by NAL in EBP rats. When norepinephrine (NE) neurotransmission was selectively suppressed by an α-adrenergic receptor blocker, phenoxybenzamine (20 μg/kg), or by dopamine-β-hydroxylase inhibitors, diethyldithiocarbamate (550 μg/kg) and bis-(4-methyl-l-homopiperazinyl thiocarbanyl)disulfide (30 μg/kg), NAL failed to stimulate LH release. Further support for adrenergic involvement in the opiate effects on LH release was evident after treatment with the NE agonist, clonidine (0.3 μg/kg). Clonidine raised serum LH levels in EBP- and EBP- and diethyldithiocarbamatetreated rats. More importantly, unlike NAL, clonidine elicited significant serum LH elevations in M-treated rats. Presumably, by bypassing opiate receptor blockade of NE neurotransmission, clonidine directly stimulated central NE receptors to elicit LH release in M-treated rats. These studies show 1) that opiates inhibit the positive feedback effects of P on serum LH and hypothalamic LHRH levels, and 2) collectively, the data are consonant with the view that modulation of LH release by opioid peptides may require NE participation.