The primary objective of the proposed research is to test the hypothesis that a alpha2-adrenergic-mu2-opioid (alpha2/mu2) receptor complex mediates the respiratory depression and development of physical dependence associated with opiate therapy whereas opiates which selectively stimulate the mu1-receptors can produce analgesia and respiratory stimulation without tolerance and physical dependence.
The specific aims of the research are: (1) To characterize the mu1 and mu2-receptor binding properties of the tetrapeptide Tyr-D-Arg2 -Phe-(NMe)Gly4 (TAPS), a proposed selective agonist at mu1-opioid receptors, and to study its effects on nociception, respiration, tolerance and withdrawal. (2) To characterize the binding capabilities of the mu1/mu2-agonists dermorphin and Tyr-D-Ala2-Gly-NMePhe4-ol5-enkephalin (DAMGO), naloxonazine (a mu1-antagonist), MR2034 (a mu2-antagonist) and rauwolscine (alpha2-antagonist) on the mu1-receptor and on the putative alpha2/mu2-receptor complex, and (3) to examine the role of the alpha2/mu2-receptor complex in mediating the opioid actions on nociception, ventilation, tolerance and withdrawal. (4) To study the contribution of the mu1-receptors and the putative alpha2/mu2-receptor complex in the mediation of opiate analgesia in tonic unavoidable pain (the formalin test) in which minimum tolerance has been shown to develop to the analgesic effect of opiates as well as in acute phasic pain (the tail-flick test) in which tolerance rapidly develops to opiate analgesia and where different neural mechanisms underlie the analgesic effect of mu-opiates. The studies will utilize established biochemical, physiological and neuropharmacological techniques (radioreceptor assays and monitoring of ventilation, analgesia and withdrawal in conscious unrestrained rats). The results of these experiments should illuminate the role of multiple mu-opioid receptors and central noradrenergic mechanisms in opioid actions. Such results might guide new therapeutic approaches to pain relief without respiratory depression and with less addictive potential.
| Vonhof, Stefan; Gudka, Bijal D; Siren, Anna Leena (2003) Tolerance and dependence following chronic intracerebroventricular infusions of Tyr-D-Arg2-Phe-Sar4 (TAPS). Eur J Pharmacol 459:41-8 |
| Vonhof, Stefan; Feuerstein, Giora; Siren, Anna-Leena (2003) Characterization of binding kinetics of [3H]Tyr-D-Arg2-Phe-Sar4 at opioid receptors. Eur J Pharmacol 473:127-34 |
| Vonhof, S; Barone, F C; Price, W J et al. (2001) Receptor binding and biological activity of the dermorphin analog Tyr-D-Arg(2)-Phe-Sar (TAPS). Eur J Pharmacol 416:83-93 |
| Paakkari, P; Paakkari, I; Vonhof, S et al. (1993) Dermorphin analog Tyr-D-Arg2-Phe-sarcosine-induced opioid analgesia and respiratory stimulation: the role of mu 1-receptors? J Pharmacol Exp Ther 266:544-50 |
| Paakkari, P; Paakkari, I; Feuerstein, G et al. (1992) Evidence for differential opioid mu 1- and mu 2-receptor-mediated regulation of heart rate in the conscious rat. Neuropharmacology 31:777-82 |
