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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040160-04
Application #
6529563
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (03))
Program Officer
Porter, Linda L
Project Start
1999-08-15
Project End
2007-07-31
Budget Start
2002-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$258,912
Indirect Cost
Name
University of North Dakota
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Santanavanich, Chorthip; Ebadi, Manuchair; Govitrapong, Piyarat (2005) Dopamine receptor activation in bovine pinealocyte via a cAMP-dependent transcription pathway. J Pineal Res 38:170-5
Shavali, Shaik; Ho, Begonia; Govitrapong, Piyarat et al. (2005) Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull 64:471-9
Chuchuen, Uayart; Ebadi, Manuchair; Govitrapong, Piyarat (2004) The stimulatory effect of mu- and delta-opioid receptors on bovine pinealocyte melatonin synthesis. J Pineal Res 37:223-9
Chetsawang, Banthit; Govitrapong, Piyarat; Ebadi, Manuchair (2004) The neuroprotective effect of melatonin against the induction of c-Jun phosphorylation by 6-hydroxydopamine on SK-N-SH cells. Neurosci Lett 371:205-8
Santanavanich, Chorthip; Chetsawang, Banthit; Ebadi, Manuchair et al. (2003) Effects of D1- and D2-dopamine receptor activation on melatonin synthesis in bovine pinealocytes. J Pineal Res 35:169-76
Govitrapong, Piyarat; Sawlom, Saiphon; Ebadi, Manuchair (2002) The presence of delta and mu-, but not kappa or ORL(1) receptors in bovine pinealocytes. Brain Res 951:23-30