Animal welfare concerns have led to increased demands for use of post-operative analgesia in association with experimental surgery. Such treatment is appropriate provided it has no effect on experimental parameters. In order to assess any effects of analgesics on endogenous melatonin production, groups of six ewes were bled at 30 min intervals for the first 4 hr of darkness a) without analgesic treatment and b) immediately after analgesic administration. Analgesics tested were ketoprofen, phenylbutazone (both non-steroidal anti-inflammatory drugs or NSAIDs) and buprenorphine (an opioid). Plasma melatonin was measured by radioimmunoassay and 4 hr secretion profiles computed for each animal. Ketoprofen and buprenorphine treatment reduced mean four hour melatonin secretion profiles by 50.6% (from 1,347.3 to 665.1 pg/ml.hr) and 38.6% (from 287.8 to 171.3 pg/ml.hr), respectively. Only in the case of phenylbutazone was the response not statistically significant; hence this drug has been selected as a post-operative analgesic for future experimental studies involving measurement of melatonin levels.
In an attempt to define the antigonadotropic activity associated with the protein/peptide extracts of ovine pineals, melatonin- and steroid-free fractions obtained after subjecting crude ovine pineal acetone powder to soft gel chromatography were tested in three bioassay systems: (1) the conventional compensatory ovarian hypertrophy inhibition assay in rats, (2) the coupled bioassay in immature mice that enables one to distinguish factors acting at the level of the pituitary from those acting at the gonadal level, and (3) the classical in vitro pituitary cell culture assay for inhibin. The large molecular weight fraction, referred to as PI, behaved like a classical antigonadotropin as it suppressed compensatory ovarian hypertrophy following unilateral ovariectomy. Further, it not only lowered the basal and gonadotropin releasing hormone (GnRH)-stimulated release of follicle stimulating hormone (FSH) by the cultured pituitary cells, but also inhibited the human chorionic gonadotropin (hCG)-induced uterine weight gain in the coupled assay, thus acting like inhibin in these two assay systems. In addition, it showed immunological cross-reactivity with ovine testicular inhibin. The present results strongly support the view that inhibin-like activity may be the major player in what has so far been referred to as antigonadotropic activity.
Both melatonin and pineal antigonadotropic peptides have the same end effect, i.e., prevention of the hypertrophic response when tested in the conventional compensatory ovarian hypertrophy (COH) model. The present work was undertaken to study the effect of melatonin and a melatonin- and steroid-free inhibin-like ovine pineal antigonadotropin (PI) on serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) following hemoiovariectomy in adult Holtzman rats and also to ascertain if any similarity exists in their mode of action during COH. While melatonin prevented the transient rise in FSH at 12 hr after unilateral ovariectomy (ULO), thus retaining the basal preoperative level, PI depressed basal levels of FSH too. In addition, melatonin suppressed PRL and LH levels at 12 hr and 120 hr after ULO, respectively. PI, on the other hand, had no effect on serum LH and PRL levels. In light of our earlier in vitro results, which showed a direct inhibitory effect of PI and not of melatonin on pituitary FSH synthesis and release, the present results indicate a dichotomy in the mode of action of PI and melatonin. PI acts directly at the level of the pituitary while melatonin may act at the level of the hypothalamus or higher brain centers to suppress the FSH surge and the ensuing compensatory response.
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