PII: S0304-3959(00)00389-4

The genesis of a nicotinic approach to pain management and the current prospects for the realization of one or more clinically viable therapeutics related thereto have been profoundly in ̄uenced by three crucial events. First was the initial ®nding by Davis et al. (1932) that nicotine was ef®cacious in a cat model of visceral pain. Ironically, virtually no research on nicotine's analgesic properties was performed over the next several decades. On the contrary, during this period, Keele and Armstrong (1964) implicated an algogenic role for nicotinic acetylcholine receptors in human skin. Although the 1980s witnessed a ̄ourish of activity on nicotine-mediated antinociception, these investigations were by and large purely heuristic, as the poor therapeutic index of nicotine relegated it to the tool chest of the pharmacologist rather than to the armamentarium of the clinician. But at the start of the next decade came the revelational discovery from the laboratory of John Daly that a trace alkaloid found in the skin of the Ecuadoran poison arrow frog, Epipedobates tricolor, produced antinociception in the mouse hot plate test (Spande et al., 1992). The compound isolated by Daly and his colleagues was called epibatidine and as an antinociceptive agent was shown to possess 200fold greater potency and equal ef®cacy compared with morphine. Like morphine and other opioids, epibatidine produced the Straub-tail response, which had been used as a bioassay during chemical puri®cation. Yet, neither this nor the antinociception produced by epibatidine were blocked by naloxone but rather by the nicotinic cholinergic receptor antagonist mecamylamine (Qian et al., 1993; Badio and Daly, 1994). Today, epibatidine is recognized as the most potent known agonist at several nicotinic receptor subtypes, an as yet incompletely identi®ed and partially localized subset of which certainly mediate its antinociceptive effects. Unfortunately, this compound is still too toxic for use in humans. Nonetheless, its antinociceptive ef®cacy and potency served to ignite considerable excitement and interest in the notion that nicotinic cholinergic receptors may represent legitimate targets in the treatment of painful conditions. The third seminal contribution, originally advanced by Bannon et al. (1998b), was the demonstration that the synthetic compound ABT-594 exhibited nicotinic receptor-mediated antinociception across animal models of both in ̄ammatory and neuropathic pain. Encouraging were initial reports indicating that ABT-594 possessed signi®cant advantages over its predecessors, particularly with regard to tolerance development (Bannon et al., 1998a), presaging the potential clinical utility of this and/or similar compounds in humans. It is important to point out that while these three contributions were instrumental in paving the way toward the current status of the ®eld of nicotinic analgesia, they were by no means the only ones (for review, see Flores and Hargreaves, 1998). Thus, the collective studies performed to date indicate that a multitude of nicotinic receptor agonists, constituting disparate pharmacological pro®les, are antinociceptive in several species, including man (Table 1). Equally impressive is that these effects have been demonstrated in a diverse array of in ̄ammatory and neuropathic pain models and comprise thermal, mechanical and chemical modalities of noxious stimulation, establishing that nicotinic agonists are both antinociceptive (capable of raising nociceptive thresholds in naIÈve animals) and antihyperalgesic (capable of reversing the reduction in nociceptive thresholds following injury). Clearly, the need for a better and safer class of analgesic drugs is warranted, as dose limiting toxicity and/or a lack of ef®cacy continue to plague existing therapies, especially with respect to treating some of the most severe and intractable painful conditions. At this point, there appear to be at least three immediately critical issues impacting the viability of a would-be nicotinic analgesic. These are toxicity, Pain 88 (2000) 1±6