Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid.

The occurrence of systematic diurnal variations in pain thresholds has been demonstrated in human. Salivary melatonin levels change following acute pain when other factors that could explain the change have been removed or controlled. Melatonin-induced analgesia is blocked by naloxone or pinealectomy. By using selective radioligands [3H]-DAMGO, [3H]-DPDPE, [3-U69593, and 3H]-nociceptin, we have shown that the bovine pinealocytes contain delta and mu, but not kappa or ORL1 opioid receptor subtypes. In the present study, by using melatonin receptor agonists (6-chloromelatonin or 2-iodo-N-butanoyl-5-methoxytryptamine) or melatonin receptor antagonist (2-phenylmelatonin), we have shown that these agents do not compete with opioid receptor subtypes. However, we observed a time-dependent release of beta-endorphin an endogenous opioid peptide, by melatonin from mouse pituitary cells in culture. Hence, it is suggested that melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by binding to its own receptors and increasing the release of beta-endorphin.

The presence of delta and mu-, but not kappa or ORL(1) receptors in bovine pinealocytes.

Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night-time. In humans, the circulating levels of melatonin, a pineal substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and low during day-time. Moreover, pinealectomy abolishes the analgesic effects of melatonin, and naloxone disrupts the day-night rhythm of nociception. In this study, we have attempted to identify and characterize the nature and types of opioid receptor in bovine pinealocyte membranes, using a radioligand binding technique with the selective radioligands [3H]DAMGO, [3H]DPDPE, [3H]U69593 and [3H]orphanin-FQ (OFQ) for identifying mu (mu)-, delta (delta)-, kappa (kappa)- and opioid receptor-like (ORL(1)) receptors, respectively. The saturation experiments on bovine pinealocyte membranes for [3H]DPDPE binding provided B(max) and K(d) values of 553+/-24 fmol/mg protein and 1.3+/-0.6 nM; and for [3H]DAMGO binding provided B(max) and K(d) values of 6.3+/-1.3 fmol/mg protein and 1.2+/-0.4 nM, respectively. On the other hand, the specific radioligands ([3H]U69593 and [3H]OFQ) binding of kappa and ORL(1) receptors were undetectable in bovine pinealocyte membranes. Furthermore, competitive experiments with opioid agonist and antagonist and related compounds confirmed the presence of mu- and delta-opioid binding sites in bovine pinealocyte membranes. These results indicate that neither kappa nor ORL(1) receptors are present on the pinealocytes, and the majority of opioid receptors found in the bovine pineal gland are delta (possibly, both delta(1) and delta(2)) types, with a minority being mu type, and that both are primarily located on the bovine pinealocyte membranes. These opioid receptors, by stimulating the activity of N-acetyltransferase, enhance the synthesis of melatonin.