Activation of -Opioid Receptors Inhibits Pruritus Evoked by Subcutaneous or Intrathecal Administration of Morphine in Monkeys

Pruritus (itch sensation) is the most common side effect associated with spinal administration of morphine given to humans for analgesia. A variety of agents have been proposed as antipruritics with poorly understood mechanisms and they are effective with variable success. -Opioid agonists possess several actions that are opposite to -opioid agonists. We proposed to investigate the role of -opioid receptors (KORs) in morphine-induced scratching and antinociception in monkeys. Scratching responses were counted by observers blinded to treatment. Antinociception was measured by a warm water (50°C) tail-withdrawal assay. Pretreatment with low doses of trans-( )-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide (U-50488H) (0.032– 0.18 mg/kg s.c.), a selective KOR agonist, dose dependently suppressed the s.c. morphine dose-effect curve for scratching and potentiated s.c. morphine-induced antinociception. In addition, s.c. U-50488H attenuated i.t. morphine (10 and 32 g)-induced scratching while maintaining or enhancing i.t. morphineinduced antinociception. The combination of s.c. or i.t. morphine with low doses of U-50488H did not cause sedation. More importantly, pretreatment with 3.2 mg/kg nor-binaltorphimine, a selective KOR antagonist, blocked the effects of s.c. U-50488H on both s.c. and i.t. morphine-induced scratching. These results indicate that activation of KOR attenuates morphine-induced scratching without interfering with antinociception in monkeys. This mechanism-based finding provides functional evidence in support of the clinical potential of KOR agonists as antipruritics in the presence of MOR agonistinduced pruritus. Application of spinal opioids is one of the significant breakthroughs in pain management during the last 2 decades. For instance, i.t. administration of morphine has been one of the most frequently used methods of analgesia after cesarean section and other surgical conditions. However, the most common side effect of spinal morphine is pruritus (i.e., itch sensation), which sometimes is severe and may lessen the value of spinal opioids for pain relief (Cousins and Mather, 1984; Ballantyne et al., 1988; Chaney, 1995; Kam and Tan, 1996). To date, there is no ideal antipruritic for patients. Several pharmacological agents have been proposed as antipruritics, but they are effective with variable success (Chaney, 1995; Kam and Tan, 1996). The mechanisms of proposed antipruritics are poorly understood, because there is a large deficiency in the basic research on spinal morphineinduced pruritus. This could be in part due to lack of reliable animal models. Although intracisternal administration of morphine evokes scratching responses in rodents, this behavior is not long lasting and is only observed at small doses that do not produce profound antinociceptive effects (Tohda et al., 1997; Ko et al., 1999b). However, high doses of i.t. morphine produce allodynia-like behaviors, but no scratching, in rats. These behaviors are not reversed by opioid receptor antagonists (Yaksh and Harty, 1988). Recently, we have established an experimental model of itch in monkeys (Ko and Naughton, 2000). We found that i.t. administration of morphine dose dependently produced longlasting scratching responses and thermal antinociception in these animals, and this parallels clinical observations This study was supported by U.S. Public Health Service Grant DA-13685 (to M.C.H.K.). Preliminary results were presented at the joint meeting of American Society for Biochemistry and Molecular Biology and American Society for Pharmacology and Experimental Therapeutics, Boston, MA, June 4 to 8, 2000 (FASEB J 14:A1318). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.044909. ABBREVIATIONS: MOR, -opioid receptor; KOR, -opioid receptor; nor-BNI, nor-binaltorphimine; MPE, maximum possible effect; U-50488H, trans-( )-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide. 0022-3565/03/3051-173–179$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 44909/1051624 JPET 305:173–179, 2003 Printed in U.S.A. 173 at A PE T Jornals on July 7, 2017 jpet.asjournals.org D ow nladed from (Baraka et al., 1981; Bailey et al., 1993; Palmer et al., 1999). In addition, results obtained from this model confirm the finding that activation of central -opioid receptors (MOR) produces scratching behavior (Thomas et al., 1992, 1993; Tohda et al., 1997; Kuraishi et al., 2000). This nonhuman primate itch model provides a valuable opportunity for itch research. It allows us to conduct further studies to elucidate both the mechanisms and potential treatments of MOR-induced pruritus. Although opioid receptor antagonists are effective in attenuating i.t. morphine-induced pruritus, they are not ideal therapeutic agents for patients. Several clinical studies have shown that spinal opioid-mediated analgesia was reversed when high doses of opioid receptor antagonists were administered to treat pruritus (Cohen et al., 1992; Saiah et al., 1994; Wang et al., 1998). Our previous study also does not support opioid receptor antagonists for treatment of pruritus, because nalmefene produced an equal reduction of both scratching and antinociception in monkeys (Ko and Naughton, 2000). Thus, one important goal of our studies is to identify specific pharmacological agents that can attenuate morphine-induced pruritus without attenuating analgesia. The -opioid receptor (KOR) agonists seem to be a prominent potential target because several studies suggest that these agents may be therapeutically useful in this area. KOR agonists have antinociceptive effects, but possess several actions that are opposite to MOR agonists (Pan, 1998). One important finding is that behavioral profiles of monkeys with KOR agonist dependence were qualitatively distinct from monkeys with morphine dependence. Specifically, scratching is very prominent as a withdrawal sign in monkeys treated chronically with a selective KOR agonist U-50488H (Gmerek et al., 1987). Many symptoms of withdrawal from opioids seem to be opposite to the acute effects of agonist administration. Excessive scratching activity indicates that acute administration of KOR agonists may have antipruritic function. Studies in rodents seem to support this notion, as systemic administration of KOR agonists inhibits scratching behavior evoked by a variety of pruritogenic agents without interfering with locomotor activity (Cowan and Gmerek, 1986; Cowan and Kehner, 1997; Togashi et al., 2002). Given that there is a possible functional interaction between MOR and KOR, it is pivotal to investigate whether activation of KOR can suppress the itching sensation while maintaining or augmenting the antinociceptive effects of i.t. morphine in primate species. The aim of this study was therefore to investigate the effects of systemic U-50488H on s.c. and i.t. administration of morphine for both scratching and antinociception. Moreover, pretreatment with a selective KOR antagonist, nor-binaltorphimine (nor-BNI), was conducted to verify whether KOR mediated the actions of U-50488H under these conditions. Materials and Methods