Direct Evidence for the Involvement of the Mesolimbic κ-Opioid System in the Morphine-Induced Rewarding Effect Under an Inflammatory Pain-Like State

Abstract

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 ...

Chronic Pain Induces Anxiety with Concomitant Changes in Opioidergic Function in the Amygdala

“…In contrast, k-opioid receptor agonist ICI 199,441-induced G-protein activation in the amygdala was significantly increased by CFA injection, but not sciatic nerve ligation. This phenomenon is consistent with our previous findings that inflammatory pain, but not nerve injury, causes a marked activation of endogenous kopioidergic system (Ozaki et al, 2002;Narita et al, 2005). At 1 week after the sciatic nerve ligation, thermal hyperalgesia and allodynia, but not an anxiogenic effect, were observed with nerve ligation.…”

“…Furthermore, this pain-like state is associated with a reduction in m-opioid receptor function in the ventral tegmental area (Ozaki et al, 2002(Ozaki et al, , 2003. We also found that an inflammatory pain-like state could cause a sustained activation of the k-opioidergic system in the nucleus accumbens, leading to suppression of the morphine-induced rewarding effect in rats (Suzuki et al, 1999;Narita et al, 2005). Taken together, these findings suggest that a state of pain may cause physiological changes in opioid transmission at supraspinal levels.…”

Comparative Pharmacological Profiles of Morphine and Oxycodone under a Neuropathic Pain-Like State in Mice: Evidence for Less Sensitivity to Morphine

“…We previously reported that morphine failed to induce rewarding effects in rats that had been injected with formalin or carrageenan into the hind paw (Suzuki et al, 1996(Suzuki et al, , 2001Narita et al, 2005a). Furthermore, it has been documented that chronic pain attenuates the development of tolerance to the antinociceptive effect of morphine in rats (Vaccarino et al, 1993).…”

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

“…Compartment A was white with a mesh floor and compartment B was black with a sand-like texture floor, but both have the same size; compartment C connected the entrances to compartments A and B, and was grey with a smooth floor. Conditioned place preference tests were performed as previously reported [18] and consisted of an 8-day schedule with four distinct phases, as follows:…”

“…Moreover, the functional interaction between these receptors has been demonstrated in cultivated tissue, where co-administration of CXCL12, CXCR4 ligand, blocks the hyperpolarizing current induced by MOR agonists in the PAG, suggesting that chemokine secretion could lead to opioid receptor desensitization, decreasing the opioid agonists effects [14]. Another report showed that the plantar pre-administration of formalin with the inflammatory response associated abolished the reward response to morphine in a conditioned place-preference model and decreased dopamine concentration in the Nac [18].…”