Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain

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Abstract

Buprenorphine is a potent opioid analgesic clinically used to treat moderate to severe pain. The present study assessed its analgesic efficacy in a broad range of rodent models of acute and chronic pain. In the phenylquinone writhing, hot plate, and tail flick mouse models of acute pain, full analgesic efficacy was obtained (ED50 values: 0.0084–0.16 mg/kg i.v.). Full analgesic efficacy was also obtained in yeast- and formalin-induced inflammatory pain (ED50 values: 0.0024–0.025 mg/kg i.v., rats and mice) and in mustard-oil-induced spontaneous pain, referred allodynia, and referred hyperalgesia in mice (ED50 values: 0.018–0.025 mg/kg i.v.). Buprenorphine strongly inhibited mechanical and cold allodynia in mononeuropathic rats, as well as mechanical hyperalgesia and cold allodynia in polyneuropathic rats (ED50 values: 0.055 and 0.036 mg/kg i.v. and 0.129 and 0.038 mg/kg i.p., respectively). It is concluded that buprenorphine shows a broad analgesic profile and offers the opportunity to treat different pain conditions, including neuropathic pain.

Introduction

Buprenorphine is a clinically well-established opioid analgesic which shows complex interactions at the various opioid receptor subtypes. It shows high affinity to μ-, δ-, κ- and ORL1-opioid receptors and slow receptor dissociation (Sadee et al., 1982). In addition, its strong potency and high lipophilicity makes buprenorphine suitable for incorporation in a transdermal formulation, which is used efficiently for the treatment of moderate to severe pain (Evans and Easthope, 2003). In vitro data generated in [35S]-GTPγS and adenylate cyclase assays (Zaki et al., 2000, Huang et al., 2001), as well as in organ bath preparations (Kajiwara et al., 1986, Lattanzi et al., 2001), characterise buprenorphine as a partial agonist at μ-opioid and ORL1 receptors and as an antagonist at κ-opioid and δ-opioid receptors. Although the extent of analgesic efficacy of partial opioid receptor agonists is discussed controversially (Wheeler-Aceto and Cowan, 1991), clinical experience indicates that the compound is a potent and efficient analgesic with a favourable side effect profile (Heel et al., 1979, Walsh et al., 1994, Evans and Easthope, 2003).

Over the years, a large body of data on the analgesic effect of buprenorphine in animals has been published. However, most of these studies were performed in animal models of acute pain (Cowan, 1995, Cowan, 2003), and it remains to be clarified to what extent the compound is effective in chronic pain models. Thus, with respect to inflammatory, visceral, and neuropathic pain, a broad and thorough preclinical assessment of the analgesic efficacy of buprenorphine appears to be lacking. In addition, variations in test protocols and routes of administration often make a direct comparison in terms of potency and efficacy difficult, and the maximal possible efficacy has not always been assessed. For example, the efficacy of buprenorphine against neuropathic pain has been tested in photochemically induced central and peripheral mononeuropathic pain without addressing maximal efficacy and effects of supramaximal doses (Kouya et al., 2002).

Preclinical studies have shown that doses of buprenorphine exceeding the maximal effective dose often lead to a decrease in analgesic efficacy (Wheeler-Aceto and Cowan, 1991), as well as in side effects (Cowan, 1992). It has been suggested that the occurrence of an inverted u-shaped (or bell-shaped) dose–response curve, as demonstrated in a mouse model of acute pain, may depend on the intensity of the stimulus used to induce pain (Lutfy et al., 2003), but the generality of this suggestion is still controversial, and the underlying mechanism of this phenomenon remains to be clarified. As it was found that combination with μ-opioid antagonists leads to a rightward shift of the inverted u-shaped curve in models of acute pain (Dum and Herz, 1981), it is possible that this peculiarity of the dose–response curve relates to the μ-opioid mechanism of the compound. Alternatively, noncompetitive autoinhibition, a model based on two receptor populations, one mediating the agonistic properties at low doses and another one mediating the antagonistic properties at high doses, was proposed as a possible molecular mechanism (Cowan et al., 1977, Sadee et al., 1982, Richards and Sadee, 1985). Beside the analgesic effect resulting from activation of μ-opioid receptors, a contribution of ORL-1 receptors has also been suggested based on results obtained with buprenorphine in ORL-1 knock-out mice (Lutfy et al., 2003). However, it should be realised that the inverted u-shaped dose–response curve has been observed only in animal models. Moreover, the apparent loss of efficacy only occurs at high doses of buprenorphine. Therefore, it can be argued that the inverted u-shaped curve observed preclinically is only of limited relevance for the clinical use of buprenorphine as an analgesic.

This study aimed at the assessment of buprenorphine's analgesic efficacy in a broad range of rodent models of acute and chronic pain, including somatic, visceral, inflammatory, and neuropathic pain. Since the experimental outcome in animal models of pain may depend on the test parameters, a broad range of stimulus qualities, such as chemical, thermal, and mechanical stimulation, as well as different stimulus intensities were selected. In some models, the effect of buprenorphine was compared with clinically relevant reference compounds. A preliminary account of the present study was reported previously (Christoph et al., 2003).

Section snippets

Animals

Male NMRI mice (20–35 g) and Sprague–Dawley rats (133–178 g), supplied by commercial breeders (Charles River, Sulzfeld, Germany, Iffa Credo, Brussels, Belgium, Janvier, Genest St. Isle, France), were housed under a 12:12 h light–dark cycle (lights on at 06:00 a.m.) and with room temperature 20–24 °C, relative air humidity 35–70%, 15 air changes per hour, and air movement <0.2 m/s. The animals had free access to standard laboratory food (Ssniff R/M-Haltung, Ssniff Spezialdiäten, Soest, Germany)

Animal models of acute pain

Buprenorphine showed dose-dependent analgesic efficacy in several mouse models of acute pain (data summarised in Table 1; outcome of repeated-measure ANOVA summarised in Table 2). Different heat stimulus intensities were used to investigate a possible influence on antinociceptive potency and efficacy. Increase in heat intensity led to decreased potency in terms of ED50 values and maximal effective dose (Fig. 1, Fig. 2A). ED50 values (95% CI) were 0.037 (0.032–0.043), 0.28 (0.26–0.33), and 0.16

Discussion

The present study investigated the analgesic efficacy of the opioid analgesic buprenorphine in a broad panel of rodent models of acute and chronic pain. The compound showed full analgesic efficacy against acute thermal and visceral pain, as well as against persistent/chronic inflammatory and neuropathic pain. Buprenorphine was more potent, and in some models also more efficient, than the clinically established reference compounds morphine, ibuprofen, and gabapentin.

Buprenorphine was found to

Acknowledgements

The authors would like to thank Jens-Otto Andreas, Stefanie Brenner, Andrea Boltersdorf, Günther Haase, Ulla Jansen, Bernhard Liebenhoff, Nadja Linnhoff, Ingrid Loeser, Simone Pfennings, Patrick Thevis, Elke Schumacher, and Hans-Josef Weber for excellent technical assistance.

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