TRK-820, a Selective κ-Opioid Agonist, Produces Potent Antinociception in Cynomolgus Monkeys

Abstract

ABSTRACT-TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid k-receptor agonist with pharmacological properties different from those produced by k 1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295-and 495-fold more potent than morphine with the 50°C and 55°C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50°C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg /kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/ kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg / kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg / kg, i.m.) and morphine (10 mg/ kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of k-opioid receptor different from the k1-opioid receptor in cynomolgus monkeys.Keywords: k-Opioid agonist, Antinociceptive effect, TRK-820, Cynomolgus monkey, k -Opioid receptor subtype Systematic efforts in searching for compounds which selectively stimulate k -opioid receptors resulted in the development of the compound TRK-820, (-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride. It has been demonstrated previously that TRK-820 possesses a highly selective k -opioid receptor agonistic activity in bioassays with isolated guinea pig ileum and mouse vas deferens preparations (1). TRK-820 is also a selective and centrally acting k-opioid agonist with antinociceptive and sedative activity in rodents (2). This is supported by the finding that the antinociception induced by TRK-820 is selectively inhibited by the pretreatment with the k -opioid receptor antagonist nor-binaltorphimine, but not by the m -opioid receptor antagonist naloxone and @-opioid receptor antagonist naltrindole. Unlike the other k-opioid agonist pentazocine, which blocks m-opioid receptors, TRK-820 has little or no m-opioid receptor antagonistic properties. In behavioral studies, TRK-820 does not produce any significant place aversion or place preference using an unbiased place preference conditioning procedure in mice (3), although other k-opioid receptor agonist...

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

“…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(Butelman et al, , 2001Ko 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.…”

“…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.…”

Opioid Kappa Receptor Selective Agonist TRK-820 (Nalfurafine Hydrochloride)

“…was also observed in cynomolgus monkeys. The analgesic effect of TRK-820 was 295 and 492-fold more potent than that of morphine in the 50 ºC and 55 ºC hot water tests, respectively, and 40 and 1000-fold more potent than that of U-50,488H and pentazocine in the 50 ºC hot water test, respectively (Table 4) (Endoh et al, 2001 (Table 5) (Endoh et al, 1999). Intravenous administration of TRK-820 was also reported to be effective in the same test (Vanderh et al, 2008).…”

k Opioids as potential treatments for stimulant dependence

“…97 Nalfurafi ne ( Figure 4 ) is a high-affi nity k agonist. 98 , 99 Further pharmacological testing has shown this compound to produce potent antinociception in nonhuman primates 100 and to be more potent than U50,488H in mice. 101 Interestingly, nalfurafi ne does not produce the psychotomimetic effects in healthy human volunteers seen with other k agonists 102 and develops lower tolerance in comparison to other k agonists.…”