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Four studies were conducted to investigate the effect and site of action of exogenous and endogenous opioids on pituitary growth hormone (GH) and prolactin (PRL) secretion in Holstein calves. In the first study, the effect of the opioid agonist DAMME (D-Ala²⁺,N-Me-Phe⁴,Met(O)⁵-01 enkephalin) on plasma GH and PRL secretion was measured in Holstein calves in fall season. Plasma concentrations of both GH and PRL increased in response to DAM ME injection. Pretreatment with either the lipid soluble opioid antagonist naloxone (NAL), which readily penetrates the blood brain barrier (BBB), or the peripherally acting antagonist methyl levallorphan mesiltate (MLM), blocked the PRL response to DAMME. Naloxone, but not MLM, negated the GH response to DAMME. In spring, the experiment was repeated with similar results. In the second experiment, the opioid antagonists NAL and MLM were administered alone to detennine whether endogenous opioids mediate basal GH and PRL secretion, and the site of action of any of opioid-mediation of basal GH and PRL. In fall, NAL administration increased both plasma GH and PRL secretion. Methyl levallorphan mesilate did not affect PRL, but increased plasma GH concentrations. In spring, a second trial using 5 different doses of each antagonist was conducted. Naloxone did not affect GH levels at any dose in spring, but decreased plasma PRL at the same dose which increased plasma PRL in fall. Plasma PRL was again unaffected by MLM, but plasma GH was increased by 3 separate doses of MLM. The third experiment was designed to determine if the increases in plasma PRL seen after DAMME administration were mediated via dopaminergic mechanisms. Plasma PRL in calves again increased in response to DAMME injection alone. In calves pre-treated with the long-acting dopamine agonist 2-Br-&alp. ergocryptine (CB 154), plasma PRL was unresponsive to DAMME injection. The pituitaries of calves treated with CB 154 in this experiment were able to respond to thyrotropin-releasing hormone (TRH) injection with increased PRL secretion. In the final experiment, the role of growth hormone-releasing hormone (GRH) in facilitating GH release after DAMME injection was investigated, and whether endogenous opioidergic mechanisms play a role in mediating the effects of exogenous GRH on GH secretion. Plasma GH concentrations increased in calves receiving either DAMME or D-ala²⁺, fragment 1- 29 amide, a synthetic GRH. The immediate increase in plasma GH concentrations after GRH injection in calves pre-treated with DAMME was approximately 5 fold less than that in calves not pre- treated with DAMME. Calves receiving DAMME and GRH in combination also produced a GH response curve with greater area under it than either compound alone, indicating possible synergism between the synthetic GRH and a DAMME-sustained release of endogenous GRH. Naloxone administration concomitantly with synthetic GRH did not alter the ability of the synthetic GRH to increase GH secretion overall, compared to synthetic GRH alone. In conclusion, these studies are the first to indicate that dairy breeds are able to respond to exogenous opioids with increased secretion of pituitary GH and PRL, as is known to occur in other mammalian species. Also, they indicate that opioid receptors mediating pituitary GH secretion to exogenous opioids in Holstein calves are located somewhere within the BBB, and those mediating PRL secretion are at a site outside the BBB. It appears from these studies that endogenous opioids within the BBB play a role in regulating basal PRL secretion, and that this regulation differs in fall and spring. A role for endogenous opioids in the regulation of GH secretion in Holstein calves may exist also, at least in fall, but the results are less conclusive. The peripheral opioid antagonist MLM alone may facilitate increased GH secretion in Holstein calves via an agonistic, not antagonistic, mechanism. These studies indicate that the increased PRL secretion seen following opioid administration in Holstein calves is mediated through a dopaminergic mechanism. It appears that endogenous opioids do not mediate the pituitary response to exogenous GRH in Holstein calves, and that GH increases after DAMME injection are facilitated, at least in part, by increased release of endogenous GRH. / Ph. D.

Four experiments were conducted to investigate the effect of naloxone, an opioid receptor antagonist, on pituitary LH secretion in Holstein cows during two periods after parturition and two phases of the estrous cycle. In experiment 1, 24 cows (12 primiparous; 12 multiparous) received either saline (n = 12) or 1 mg/kg naloxone (n = 12) i. v. at 14 1 days postpartum. Blood samples were collected at 15-minute intervals for 2 hours before and 2.5 hours after naloxone or saline. Serum LH concentrations increased (P < .05) in response to naloxone injection in both primi- and multiparous cows. Saline injection did not affect LH concentrations. In experiment 2, 27 cows (13 primiparous; 14 multiparous) received either saline (n=14) or 1 mg/kg naloxone (n=13) i. v. at 28 ± 1 days postpartum. Blood samples were collected as in the previous experiment. Naloxone did not affect serum LH concentrations in either primi- or multi-parous cows at 28 days postpartum. In experiment 3, estrous cycles were synchronized via prostaglandin administration (25 mg) in 22 cows (10 primiparous; 12 multiparous). Cows received either saline (n=11) or 1 mg/kg naloxone (n=11) Lv. during the luteal phase of the estrous cycle. Blood samples were collected as in the previous experiments. Luteinizing hormone concentrations were not affected by naloxone in either primi- or multi-parous cows during the luteal phase of the estrous cycle. In experiment 4, the same cows used in experiment 3 received a second dose of prostaglandin (25 mg). Thirty-six hours later, during the follicular phase of the estrous cycle, the cows received either saline (n =9) or 1 mg/kg naloxone (n = 11) i. v. Naloxone increased (P < .05) serum LH concentrations in both primi- and multi-parous cows in the follicular phase. These results suggest that LH release in the early postpartum dairy cow is regulated, at least in part, by endogenous opioid pep tides , and the ability of naloxone to affect LH secretion may change as days postpartum increases, perhaps due to changes in degree of inhibition by endogenous opioid peptides, and (or) changes in serum progesterone concentration due to onset of ovarian activity during postpartum period. It appears that the modulation of LH secretion may be mediated via opioids during the follicular phase of the estrous cycle. However, an opioid-mediated mechanism for modulation of LH secretion was absent or overridden by progesterone feedback during the luteal phase of the estrous cycle. / Master of Science