Research reportEffects of multiple intracerebroventricular injections of [d-Pen2,d-Pen5]enkephalin and [d-Ala2,Glu4]deltorphin II on tolerance to their analgesic action and on brain δ-opioid receptors
Introduction
It is now well accepted that opioid drugs produce their analgesic action by interacting with three major types of receptors, namely μ, δ, and κ. The agonists at these receptors on chronic administration produced tolerance to their analgesic actions. The molecular mechanisms involved in the production of tolerance are not well delineated, although they may involve first, second or even the third messenger systems [2]. In general it has been reported that tolerance is associated with down-regulation of the specific receptors in the brain and/or spinal cord [1]. Much attention has been paid to the existence of subtypes of each of the opioid receptors. Considerable evidence has been presented for the existence of δ1- and δ2-opioid receptors as δ-opioid receptors subtypes. The agonists at these receptors are [d-Pen2,d-Pen5]enkephalin (DPDPE) and [d-Ala2,Glu4]deltorphin II (deltorphin II), respectively [13]. This classification is based upon the fact that there is a lack of cross-tolerance between DPDPE and deltorphin II [13]. Differential antagonism of δ-opioid receptor agonists, DPDPE and deltorphin II — induced analgesia by the irreversible δ1- and δ2-opioid receptor antagonists, [d-Ala2,Leu5,Cys6]enkephalin and naltrindole-51-isothiocyanate, respectively, also suggested the possibility of δ-opioid receptor subtypes [9].
Further behavioral evidence for the heterogeneity of δ-opioid receptors was obtained when chronic administration of highly selective δ1 antagonist, 7-benzylidene-7-dehydronaltrexone (BNTX) enhanced the analgesic response to DPDPE but not to deltorphin II. Similarly, chronic administration of naltriben, a highly selective δ2-opioid receptor antagonist enhanced the analgesic response to deltorphin II but not to DPDPE [6].
On the other hand, there have been instances where δ1- and δ2-opioid receptor could not be distinguished. For instance, tolerance to both DPDPE and deltorphin II could be blocked by N-methyl-d-aspartate (NMDA) receptor antagonists 3, 15but not by nitric oxide synthase inhibitors 4, 16. Similarly, NMDA receptor antagonists have been shown to antagonize both δ1- and δ2-opioid receptor agonist-induced antinociception in mice [5].
In order to further assess the heterogeneity of δ-opioid receptors, the present studies were carried out to determine the effects of twice daily i.c.v. injections of DPDPE and deltorphin II for 2 or 4 days durations on the tolerance development as well brain δ-opioid receptor labeled with [3H]DPDPE.
Section snippets
Animals
Male Swiss–Webster mice weighing 25–30 g (Sasco King Animal Co., Oregon, WI) were housed five to a cage in a room with controlled temperature (23±1°C), humidity (50±10%) and light (06.00 h–18.00 h) for at least 4 days before being used. Food and water were made available continuously.
Chemicals
DPDPE, deltorphin II and [3H]DPDPE (specific activity 18 Ci/mmol) were obtained from the Research Technology Branch, National Institute on Drug Abuse, Rockville, MD, through the courtesy of Mr. Kevin Gormley. DPDPE
Effects of multiple injections of [d-Pen2,d-Pen5]enkephalin or deltorphin II on tolerance to their analgesic action
Multiple i.c.v. injections of DPDPE resulted in the development of tolerance to its analgesic action in mice. After 2 days of twice daily injections, the analgesic response to DPDPE (10 μg per mouse) in mice was decreased by 44% (P<0.05) in comparison to vehicle injected control mice (Fig. 1A). After 4 days of twice daily injections, the analgesic response to DPDPE was decreased by 76% (P<0.01) in comparison to vehicle injected control mice (Fig. 1B).
Multiple i.c.v. injections of deltorphin II
Discussion
The present studies were designed to assess the impact of treatment with DPDPE and deltorphin II, the two selective ligands for δ1- and δ2-opioid receptor, for different duration on the tolerance development as well as changes in the brain δ-opioid receptor in the mouse. Additionally, the impact of chronic treatment with δ2-opioid receptor agonist on the brain δ1-opioid receptor was also determined. Clearly in the present investigation both δ1- and δ2-opioid receptor agonists on chronic i.c.v.
Acknowledgements
These studies were supported by Grant DA-08867 and a Research Scientist Development Award, K02-DA-00130, from the National Institute on Drug Abuse. The authors thank Mrs. Celina Tejada for secretarial assistance.
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