Influence of prazosin and clonidine on morphine analgesia, tolerance and withdrawal in mice

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Abstract

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (α2-adrenoceptor agonist) and prazosin (α1-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another α1-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of α2-adrenoceptors in opioid actions, also α1-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

Introduction

Pain modulation is a dynamic process, which involves many interactions among complex ascending and descending neuronal systems. Opioidergic and noradrenergic pathways have very important roles in nociception and analgesia Childers, 1991, Furst, 1999, Summers and McMartin, 1993. Activation of opioid and α2-adrenergic receptors inhibits the transmission of pain sensation at spinal and supraspinal levels. While α2-adrenoceptors inhibit nociception and have analgesic synergy with opioids, there is evidence that α1-adrenoceptors may facilitate nociception and oppose opioid analgesia. Microinjection of the α1-adrenoceptor antagonist, prazosin, into the nucleus raphe magnus, a brain nucleus involved in nociceptive processing, produces antinociception similar to the α2-adrenoceptor agonist clonidine (Sagen and Proudfit, 1985). It has also been reported that prazosin augments clonidine analgesia in amphibians (Brenner et al., 1994). Morphine microinjection into the ventrolateral periaqueductal gray inhibits nociceptive tail responses, an effect mediated by acetylcholine, 5-HT and α2-adrenergic receptors in the spinal cord. In some experiments, however, microinjection of morphine into the periaqueductal gray has also facilitated nociceptive responses; this facilitation of hot plate responses was mediated by α1-adrenoceptors in the spinal cord (Holden et al., 1999).

Rapid development of tolerance and dependence limits the usefulness of morphine and other potent opioids in long-term treatment. Morphine tolerance and dependence are complex phenomena, involving also the brain noradrenergic system Harrison et al., 1998, Milanes and Laorden, 2000. Tolerance also develops to the analgesic activity of clonidine. The analgesic and sedative effects of α2-adrenoceptor agonists are attenuated in chronic administration, and there is cross-tolerance between morphine and α2-adrenoceptor agonists Roerig, 1995, Ware and Paul, 2000. Clonidine has been used clinically for treatment of opioid withdrawal. There is very limited information on the possible involvement of α1-adrenoceptors in opioid tolerance, dependence and withdrawal.

Selective α1-adrenoceptor antagonists may thus potentiate morphine analgesia and have potential to counteract some of the undesired effects of morphine. Prazosin is a relatively selective α1-adrenoceptor antagonist. High doses of prazosin also block α2-adrenoceptors but with less potency at α2A-adrenoceptors, compared to α2B- and α2C-adrenoceptors. In this study, the effects of acute administration and chronic pretreatment with different doses of prazosin on morphine analgesia, tolerance and withdrawal were examined to clarify the importance of α1-adrenergic receptor activation in modulation of opioid effects. The involvement of α2-adrenoceptors in these processes was also investigated with use of the classical α2-adrenoceptor agonist, clonidine, similarly employed as single and repeated doses.

Section snippets

Animals

Male C57 Bl/6 J mice weighing 22–35 g were used. Animals were allowed free access to food and tap water, and were kept under artificial light for 12 h each day and in a room with controlled temperature (21 °C) and humidity (50±10%). All experiments were approved by the local committee for animal welfare and were in accordance with the European Communities Council Directive of 24 November 1986 (86/906/EEC). Each mouse was tested only once. The group n was 9 to 10.

Drugs

Morphine HCl (Sigma), prazosin

Acute prazosin potentiated morphine analgesia and opposed morphine tolerance

Prazosin given alone had no analgesic effect, neither in drug-naive (Fig. 1A) nor in morphine-treated mice (result not shown). Single doses of prazosin administered 30 min before a test dose (5 mg/kg) of morphine increased the analgesic efficacy of the morphine test dose, as evidenced by increased reaction latencies in the tail-flick test (up to 84±5% and 90±4% of MPE after 0.25 and 0.5 mg/kg, compared to 38±1% of MPE in the control group receiving only morphine) (Fig. 1A). Another α1

Discussion

The α2-adrenoceptor agonist employed in the present experiments, clonidine, is known to have analgesic efficacy and to potentiate morphine analgesia. In this study, clonidine also appeared to attenuate the expression of morphine tolerance and withdrawal upon acute administration. The interpretation of these results is, however, complicated by the analgesic and sedative properties of α2-adrenoceptor agonists (Buerkle and Yaksh, 1998). Chronic clonidine pretreatment did not prevent the emergence

Acknowledgements

The authors wish to express their gratitude to Dr. Aapo Honkanen for support.

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