Buprenorphine: a unique drug with complex pharmacology - PubMed (original) (raw)

Buprenorphine: a unique drug with complex pharmacology

Kabirullah Lutfy et al. Curr Neuropharmacol. 2004 Oct.

Abstract

Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.

Keywords: Buprenorphine; ORL-1 receptors; agonist-antagonist; antinociception; dependence; knockout mice; partial agonist; tolerance.

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Figures

Fig. (1)

Fig. (1)

Buprenorphine attenuates morphine-induced antinociception in wild type, but not ORL-1 receptor knockout, mice in the radiant heat tail flick assay. Mice were tested for baseline tail flick latency, injected with morphine (2.5 mg/kg, s.c.) and tested 30 min later. The same mice were injected with the next dose of morphine (5 mg/kg,) and tested 30 min later. After the tail flick latency was measured 30 min following the last dose of morphine (10 mg/kg, s.c.), mice were injected with buprenorphine (3 mg/kg, s.c.) and tested after a further 15-min delay. Data are means (± s.e.m.) of 5–6 mice/genotype. *indicates a significant difference between wild type (WT) and knockout (KO) mice (t = 4.07; p<0.05).

Fig. (2)

Fig. (2)

Tolerance develops to the antinociceptive effect of buprenorphine in mice lacking the ORL-1 receptor in the radiant heat tail flick assay. Mice were injected with either saline or buprenorphine (1 mg/kg, s.c.) once daily for 4 days. On day 5, mice were tested for baseline tail flick latency, injected with buprenorphine (1 mg/kg, s.c.) and re-tested after 15 min. Percent maximum possible effect (%MPE) was obtained using the formula: %MPE = [(Test latency − Baseline) / (Cut-off (15 sec) − Baseline)] × 100. Data are means (+ s.e.m.) of 5–7 mice/treatment/group.

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