Introduction: Opioids remain the mainstay for the treatment of moderate to severe pain. However, whereas they have good efficacy for nociceptive pain their efficacy in neuropathic pain is limited, typically requiring much larger doses. These doses are associated with an increased occurrence of side-effects (cognitive impairment, respiratory depression, and constipation), rapid tolerance development, and opioid-induced hyperalgesia [1]. A potential approach to enhance opioid efficacy in neuropathic pain is to combine an opioid with another agent to produce a synergistic analgesic effect while minimizing side-effects, tolerance development, and hyperalgesia [2]. Two potential drug classes for combining with opioids are: 1) N-methyl-D-aspartate (NMDA) receptor antagonists, and 2) nicotinic acetylcholine receptor (nAChR) agonists. Objective: We have characterized the preclinical pharmacology of a novel NMDA-receptor antagonist, norketamine, as well as a novel nAChR agonist, nornicotine, in combination with morphine (mu-receptor opioid agonist). Method: Specifically, morphine (3mg/kg) was combined with S-norketamine (0.01, 01, 1mg/kg) or S-nornicotine (0.01, 0.05, 0.5mg/kg) and studied utilizing a rodent model of neuropathic pain, the chronic constriction nerve injury model (CCI). Responsiveness to mechanical noxious stimuli (antihyperalgesic effect) was assessed using the paw-pressure test in Sprague-Dawley male rats [3]. Results: S-norketamine and S-nornicotine, in doses that were not antihyperalgesic by themselves, dose-dependently potentiated the effect of morphine against mechanical hyperalgesia. Thus, combining morphine (3mg/kg) with S-norketamine (1mg/kg) or S-nornicotine (0.5mg/kg) resulted in the maximum possible effect (%MPE=100%). To achieve a similar antihyperalgesic effect typically requires approximately a three-fold higher dose of morphine alone (10mg/kg). Conclusion: An enhanced antihyperalgesic effect has been observed by combining morphine and a NMDA-receptor antagonist, S-norketamine, or a nAChR agonist, S-nornicotine, in a rat model of neuropathic pain (CCI). The results of this preclinical study may be of importance in the development of novel opioid combination drug therapy(ies) with less toxicity for the treatment of neuropathic pain.