Recent clinical studies have demonstrated that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. The present study was undertaken to ascertain the modulation of psychological dependence on morphine under a chronic pain-like state in rats. The prototypical m-opioid receptor agonist morphine (8 mg/kg, i.p.) induced a dose-dependent place preference. In the present study, we found that an inflammatory pain-like state following formalin injection significantly suppressed the morphine-induced rewarding effect. This effect was almost reversed by s.c. pretreatment with the k-opioid receptor antagonist norbinaltorphimine (nor-BNI, 5 mg/kg). Furthermore, the morphine-induced increase in dopamine (DA) turnover in the limbic forebrain was significantly inhibited by treatment with formalin. This inhibition was also suppressed by pretreatment with nor-BNI. In addition, in vivo microdialysis studies clearly showed that the morphine-induced increase in the extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in the nucleus accumbens (N.Acc.) was significantly decreased in rats that had been pretreated with formalin. This effect was in turn reversed by the microinjection of a specific dynorphin A antibody into the N.Acc. These findings suggest that the inflammatory pain-like state induced by formalin injection may have caused a sustained activation of the kopioidergic system within the N.Acc., resulting in suppression of the morphine-induced rewarding effect in rats. The present study provides further evidence of the clinical usefulness of morphine in patients suffering from severe pain. Neuropsychopharmacology (2005) 30, 111-118, advance online publication, 14 July 2004; doi:10.1038/sj.npp.1300527Keywords: opioid; inflammatory pain-like state; morphine dependence; nucleus accumbens; rat INTRODUCTIONThe World Health Organization publication Cancer Pain Relief (WHO, 1996) proposed a method for the relief of cancer pain based on a small number of relatively inexpensive drugs, including morphine. This approach is now used worldwide.Recent clinical experience has shown that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern (WHO, 1996). However, undue anxiety about psychological dependence on morphine in cancer patients has caused physicians and patients to use inadequate doses of opioids. Nociceptive stimuli produced physiological changes in the levels of some proteins and neuropeptides in dorsal horn neurons (Dubner and Ruda, 1992;Narita et al, 2000). We reported previously that morphine failed to induce rewarding effects under a neuropathic pain-like state induced by sciatic nerve ligation in the rat and mouse (Ozaki et al, 2002(Ozaki et al, , 2003. Furthermore, this pain-like state leads to a reduction in m-receptor function in the ventral tegmental area (VTA; Ozaki et al, 2002Ozaki et al, , 2003, which is the origin of the mesolimbic dopaminergic system and the major ...

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