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Chronic pain remains one of the most challenging of all neurologic diseases and, currently approved drugs have only a modest efficacy in several patient groups and numerous side effects. In recent years, a variety of structurally distinct α7 nicotinic acetylcholine receptor (nAChR) agonists have been developed and profiled for a variety of neurologic diseases. In particular, some of these agonists have been shown to have therapeutic significance in reducing inflammation and nociception, as well as in providing neuroprotection in animal models.1-8 The α7 nAChRs were targeted because they are expressed on both supraspinal and spinal pain transmission pathways.9-14 These receptors are also found on immune and nonimmune cytokine-producing cells, such as macrophages and keratinocytes.15 However, there are still a number of uncertainties in the development of α7 nAChR agonists for the treatment of pain, including receptor selectivity (namely cross-reactivity with 5-HT3 receptors, which have high homology with α7 nAChRs) and possible adverse effects.16,17 In addition, although α7 nAChR agonists have shown beneficial effects in chronic pain models in some studies, this effect was not consistently seen in other studies.18 An alternative therapeutic approach has been the development of positive allosteric modulators (PAMs), which can synergize and augment orthosteric-site–mediated signaling of endogenous neurotransmitters, including acetylcholine and choline, without, in most cases, directly activating or desensitizing the receptor. Several selective α7 nAChR PAMs have been reported and classified as type I and type II. Type I PAMs increase peak agonist-evoked responses, but have little or no effect on the decay rate of macroscopic currents or the equilibrium desensitization of α7 nAChRs, whereas type II PAMs both increase peak currents and slow down the apparent desensitization profile of the agonist response and/or recover nAChRs from the desensitized state.19,20 Both PAM types have been recently tested in vivo for their efficacy in animal models of inflammation and neuropathic pain; however, type II but not type I PAMs were shown to be effective in neuropathic pain models.21,22 Most studies with α7 nAChR PAMs in chronic pain models were conducted with PNU-120596,21-24 and more recently with the newly reported 2,4,20,50-tetrahydroxychalcone.25 Hence, additional studies are needed to fully explore and investigate the analgesic-like properties of α7 nAChR PAMs in animal models of chronic pain. Therefore, in this study, we sought to evaluate the anti-nociceptive and antiinflammatory effects of 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a novel and putative selective α7 nAChR type II PAM,26,27 using different mouse models of chronic pain. PAM-2 has recently been found to enhance α7 nAChR activity in vitro26 and to produce antidepressant activity in mice in vivo.27 The first aim of this study was to evaluate whether PAM-2 produces antiallodynic or antihyperalgesic activities in several mouse inflammatory and neuropathic pain models. We also assessed the effects of PAM-2 on aversion, an important affective component of pain.