Present treatment for acute and/or chronic pain rely on non-steroidal anti-inflammatory agents and narcotic analgesics. However, there are various persistent painful conditions such as neurodegenerative diseases that respond poorly to existing analgesics and hence await novel therapeutic avenues. Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In human, 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 very low during day times. Moreover, melatonin exhibits maximal analgesic effects at nights, pinealectomy abolishes the analgesia effects of melatonin, and opioid receptor antagonists disrupt the day-night rhythm of nociception. Since delta opioid receptors modulate the release of substance P, the first specific aim of this proposal is to search for and characterize delta one and two opioid receptor subtypes in bovine pinealocytes, using [D-Ala2-,N-MePhe4,Gly-ol5]enkephalin and [D-Pen2,5]enkephalin. Since cross-tolerance exists between mu opioid and alpha-2 adrenergic receptors, but not between mu and delta receptors, the second specific aim of this proposal is to characterize the specific nature of the mu and delta receptors, differentially coupled to G protein subtypes in pineal membranes. Since addition to narcotic alters the kinetic parameters of D1 and D2 dopaminergic receptors in the brain, the third specific aim of this proposal are to determine the nature of dopamine transporters in bovine pineal gland by using [3H]GBB-12935 and autoradiography and to delineate the expression of D1 and D2 dopamine receptor mRNA by employing in situ hybridization histochemistry. Since melatonin may behave as a mixed opioid receptor agonist-antagonism, it is doubtful that physician simply could potentiate the analgesic efficacy of narcotics such as morphine by co-administering melatonin. Therefore, future research must synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.
