Effects of Atypical -Opioid Receptor Agonists on Intrathecal Morphine-Induced Itch and Analgesia in Primates

Itch/pruritus is the most common side effect associated with spinal administration of morphine given to humans for analgesia. The aim of this study was to investigate the effectiveness of -opioid receptor (KOR) agonists with diverse chemical structures as antipruritics and to elucidate the receptor mechanism underlying the antipruritic effect in monkeys. In particular, previously proposed non-KOR-1 agonists, including nalfurafine [TRK-820, 17-cyclopropylmethyl-3,14 -dihydroxy-4,5 -epoxy6 -[N-methyl-trans-3-(3-furyl)acrylamido]morphinan], bremazocine [( )-6-ethyl-1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol], and GR 89696 [4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1piperazinecarboxylic acid methyl ester] were studied in various behavioral assays for measuring itch/scratching, analgesia, and respiratory depression. Systemic administration of nalfurafine (0.1–1 g/kg), bremazocine (0.1–1 g/kg), or GR 89696 (0.01–0.1 g/kg) dose-dependently attenuated intrathecal morphine (0.03 mg)-induced scratching responses without affecting morphine antinociception. The combination of intrathecal morphine with these KOR agonists did not cause sedation. In addition, pretreatment with effective antiscratching doses of nalfurafine, bremazocine, or GR 89696 did not antagonize systemic morphine-induced antinociception and respiratory depression. The dose-addition analysis revealed that there is no subadditivity for nalfurafine in combination with morphine in the antinociceptive effect. Furthermore, the KOR antagonist study revealed that antiscratching effects of both nalfurafine and a prototypical KOR-1 agonist, U-50488H [trans-( )-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)-benzeneacetamide], could be blocked completely by a selective KOR antagonist, nor-binaltorphimine (3 mg/kg). These findings suggest that the agonist action on KOR mainly contributes to the effectiveness of these atypical KOR agonists as antipruritics, and there is no evidence for KOR subtypes or -opioid antagonist action underlying the effects of these KOR agonists. This mechanism-based study further supports the clinical potential of KOR agonists as antipruritics under the context of spinal opioid analgesia. Spinal administration of -opioid receptor agonists is an important method for pain management. In particular, it is a widely used therapy for obstetric analgesia (Cousins and Mather, 1984; DeBalli and Breen, 2003). However, itch/pruritus is the most common side effect of spinal opioid administration, and it reduces the value of spinal opioids for pain relief (Cousins and Mather, 1984; Ganesh and Maxwell, 2007). Previous studies have demonstrated that the same -opioid receptors mediate both analgesic and itch/scratching responses in primates (Ko and Naughton, 2000; Ko et al., 2004). Therefore, opioid receptor antagonists such as naloxone are not ideal antipruritics to be used under this context because such compounds can reverse opioid analgesia concurrently (Rawal et al., 1986; Cohen et al., 1992; Wang et al., 1998). It is important to identify specific pharmacological agents that can inhibit spinal opioid-induced itch without attenuating analgesia. The -opioid receptor (KOR) seems to be a promising target because several studies suggest that KOR agonists are potentially useful as antipruritics. For example, scratching was a prominent withdrawal sign in monkeys treated chronically with and withdrawn from a selective KOR agonist, U-50488H (Gmerek et al., 1987). Many withdrawal symptoms from opioids appear to be opposite to the acute effects of agonist administration (Heishman et al., 1989; Kishioka et This study was supported by United States Public Health Service [Grant DA-013685]; and by Taiwan National Science Council [Grants NSC-96-2413H-004-019, NSC-97-2628-H-004-089-MY2]. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.143925. ABBREVIATIONS: KOR, -opioid receptor; U-50488H, trans-( )-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide; nalfurafine (TRK-820), 17-cyclopropylmethyl-3,14 -dihydroxy-4,5 -epoxy-6 -[N-methyl-trans-3-(3-furyl)acrylamido]morphinan; nor-BNI, nor-binaltorphimine; bremazocine, ( )-6-ethyl-1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol; GR 89696, 4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxylic acid methyl ester. 0022-3565/09/3281-193–200$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 328, No. 1 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 143925/3417347 JPET 328:193–200, 2009 Printed in U.S.A. 193 at A PE T Jornals on Sptem er 3, 2017 jpet.asjournals.org D ow nladed from al., 2000). Excessive scratching activity observed during KOR withdrawal indicates that acute administration of KOR agonists may have antipruritic effects. Animal studies seem to support this notion because systemic administration of KOR agonists inhibited scratching evoked by pruritogenic agents without interfering with locomotor activity in rodents (Cowan and Gmerek, 1986; Togashi et al., 2002). In addition, KOR agonists can prevent or reverse intrathecal morphineinduced itch/scratching responses without interfering with intrathecal morphine analgesia in monkeys (Ko et al., 2003a). More importantly, animal studies have led to a successful clinical trial of a novel KOR agonist, nalfurafine (TRK-820), in hemodialysis patients suffering from uremic pruritus, supporting the therapeutic potential of KOR agonists as antipruritics (Wikström et al., 2005). It is interesting that KOR antagonist studies have indicated that KOR-mediated antinociceptive effects may occur through two KOR subtypes. This distinction between KOR-1 and non-KOR-1 agonists is derived primarily from the differential susceptibility of KOR agonists to a KOR antagonist, nor-binaltorphimine (nor-BNI), and other opioid receptor antagonists, such as naltrexone in primates (Butelman et al., 1993; Ko et al., 1998). Prototypical KOR-1 agonists such as U-50488H are more sensitive to the antagonist effects of nor-BNI and naltrexone (Butelman et al., 1993; Ko et al., 1998). In contrast, other KOR agonists, including nalfurafine, bremazocine, and GR 89696, are less sensitive to the antagonist effects of nor-BNI and naltrexone (Butelman et al., 1993, 2001; Ko et al., 1998; Endoh et al., 2001). Although there is only one KOR cloned, and it appears to resemble the KOR-1 (Simonin et al., 1995), additional studies are needed to understand the relevant functions of KOR across different behavioral assays. In particular, non-KOR-1 agonists have atypical KOR pharmacological properties, including low to moderate affinity for -opioid receptors and extremely high potency in vivo (Toll et al., 1998; Butelman et al., 2001; Endoh et al., 2001). It is pivotal to investigate the effectiveness of these atypical KOR agonists as antipruritics and to elucidate the receptor mechanisms underlying the antipruritic actions of these KOR agonists. Intrathecal administration of a single dose of morphine produces both itch/scratching and antinociception simultaneously in monkeys (Ko and Naughton, 2000; Ko et al., 2003a). This finding parallels closely with the behavioral effects of spinal administration of morphine in humans (Bailey et al., 1993; Palmer et al., 1999). It is valuable to use this experimental model of itch to characterize effects of novel compounds in monkeys for translational research. Therefore, the aim of this study was to investigate the effectiveness of atypical KOR agonists with diverse chemical structures as antipruritics against intrathecal morphine-induced itch and analgesia. Using different pharmacological approaches, studies were conducted to elucidate the receptor mechanisms underlying the antipruritic actions of these KOR agonists under this context. Materials and Methods