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Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's antinociceptive potency and simultaneously attenuates opioid tolerance and dependence. These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine's analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.

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Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NIX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca2+-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses ofNLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability.Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development ofwithdrawal symptoms in chronic, as well as acute, physical dependence assays.Many clinical reports have noted the unexpected and paradoxical observation that administration of low doses (<30 ,ug/kg) of the opioid antagonist naloxone (NLX) results in analgesia or enhances, rather than attenuates, the analgesic effects of morphine or other opioid agonists (refs. 1-8; see reviews in refs. 9 and 10). Similarly, low doses of NLX induce analgesia in normal and especially in arthritic rats, whereas only high doses elicit hyperalgesia (11)(12)(13)(14)(15)(16)(17). "Paradoxical" analgesia is also induced in rats by a brief series of daily injections of NLX or naltrexone (NTX) (18-21). The mechanism underlying NLX-induced analgesia and NLX enhancement of morphine-induced analgesia is unknown, although some studies have suggested that low-dose NLX may selectively block a putative opioid system that is antagonistic to analgesia (9, 10) or an endogenous dynorphin "antianalgesic system" (22). NLX may also elicit analgesia by blocking specific K opioid-mediated hyperalgesic systems in the central nervous system (ref. 23; see also refs. 24-27).Electrophysiologic studies of opioid effects on nociceptive types of dorsal root ganglion (DRG) neurons in culture have led us to propose that just as Gi/G.-coupled inhibitory opioid...