The Hypothalamic Peptides, β‐Endorphin, Neuropeptide K and Interleukin‐1β, and the Opiate Morphine, Enhance the Excitatory Amino Acid‐Induced LH Release under the Influence of Gonadal Steroids
Authors: Bonavera J. J. , Sahu A. , Kalra S. P. , Kalra P. S. 
Published: September 2006

Several hypothalamic neuropeptides and amino acids are known to inhibit or excite pituitary luteinizing hormone (LH) release, but the precise interplay between these 2 classes of signals in episodic LH discharge is not known. In this study, we have evaluated the interaction between neuropeptides shown previously to inhibit LH release in castrated rats and the excitatory amino acid agonist, N‐methyl‐D‐aspartate (NMDA), on LH release in intact male rats. Rats received a permanent intracerebroventricular (i.c.v.) cannula and 9–12 days later an intrajugular cannula for frequent blood sampling. The next day, rats received i.c.v. either saline (SAL, 3 μl, controls) or a neuropeptide: the opioid β‐endorphin (β‐END; 2.9 nmol), the tachykinin neuropeptide K (NPK, 2.5 nmol) or the cytokine interleukin‐1β (IL‐1β, 5.9 pmol) in SAL. The LH response to 2 consecutive i.v. injections of NMDA (5 mg/kg) at 30 min intervals was evaluated. In control rats, each NMDA injection evoked a significant release of LH at 10 min. Quite unexpectedly, the three peptides, instead of exerting an inhibitory effect, enhanced the LH response to NMDA. The peak plasma LH levels after each NMDA injection and the cumulative LH responses were significantly higher in peptide‐treated than in control rats. This peculiar ability of the peptides that inhibit LH release in castrated rats, to potentiate the NMDA‐induced LH release in the presence of gonadal steroids was further validated in female rats treated with an opiate receptor agonist, morphine (MOR) which is also known to suppress LH release in ovariectomized rats. Rats were ovariectomized (ovx) and 14 days later received one estradiol‐17β‐containing Silastic® capsule s.c. (E2, 300 μg/ml oil). In addition, each rat received 1 pellet of placebo (PLA, control) or MOR (75 mg/pellet) s.c. followed 2 days later by 2 additional PLA or MOR pellets, and an intrajugular cannula. The LH response of these rats to 2 i.v. injections of NMDA (5 mg/kg) 30 min apart was evaluated. The results showed that each injection of NMDA elicited a pulse of LH with peak levels at 10 min in control rats. However, in MOR‐treated rats the LH response to NMDA was amplified; peak and cumulative LH responses were significantly higher in these rats. To ascertain whether this augmentation of LH response induced by MOR was exerted at the hypothalamic level, the effects of NMDA on in vitro LHRH release from the median eminence‐arcuate nucleus (ME‐ARC) fragment of ovx rats similarly pretreated with E2 and PLA or MOR were compared. The results showed that LHRH efflux in response to 50 mM NMDA alone and in combination with 23 mM KCl was higher in MOR‐treated than in control rats. Cumulatively, these results show that activation of hypothalamic opioid, tachykinin and cytokine receptors which ordinarily result in suppression of LH release in gonadal steroid deficient rats, concurrently enhances the excitatory LH response of NMDA under the influence of gonadal steroids. These unexpected findings reveal a novel modality of involvement of these peptides in the hypothalamic control of pituitary LH release. While these peptides may play a role in attenuating LH secretion in intact rats, our studies are in accord with the view that these peptides enhance the response of the hypothalamo‐pituitary axis to incoming signals, including the excitatory amino acids, that excite the release of LH.