New Research Areas

The identification clinically useful analgesic targeting nonopioid mechanisms has been challenging as demonstrated by the failure of several novel tachykinin NK-1 receptor antagonists in clinical trials.39 Other novel analgesic agents have either not been advanced or are used in only limited conditions due to mechanism related toxicities. For example, the analgesic efficacy of ziconotide, a selective neuronal calcium channel (N-type, Cav2.2) blocker (discussed in more detail below) is limited to intrathecal administration in order to minimize severe cardiovascular adverse effects. Additionally, the development of several classes of adenosine kinase inhibitors as analgesics was halted due to the occurrence of vascular microhemorrhages in brain.60 Despite these difficulties in translating advances in pain neurobiology into clinical useful analgesics, a number of novel analgesic mechanisms and compounds have been identified and validated in preclinical models. Some of these are described below. Neuronal Nicotinic Receptor Agonists

Activation of neuronal nicotinic receptors (NNRs) represents a novel approach to pain management supported by the observation that epibatidine (isolated from Epipedobates tricolor) had significantly greater analgesic potency than morphine in assays of acute thermal pain.61,62 While the mechanism of action of epibatidine was unknown, it was subsequently found to be a picomolar agonists at NNRs. NNR agonists with higher affinity for the a4b2 subunit (the predominant subtype in the CNS) relative to the aipiSy nicotinic acetylcholine receptor subunit (located at the neuromuscular junction) had analgesic efficacy with a larger therapeutic window from severe side effects than did epibatidine.63-67 These observations facilitated the discovery of ABT-594 (Figure 7), an a4b2-preferring NNR agonist that was synthesized independently of the identification of the mechanism of action of epibatidine. ABT-594 has broad-spectrum analgesic activity in both acute (hot plate, tail flick, formalin) inflammatory (CFA), and neuropathic pain models. Importantly, ABT-594 showed less potential for analgesic tolerance than morphine in animal models and did not produce pharmacologic dependence.63-65 Vanilloid Receptor Modulators

The analgesic actions of topically applied capsaicin, the active ingredient in hot chillies, has been known for many years; however, the clinical utility of vanilloid-derived analgesics has been limited by the initial burning sensation these

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