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

Abstract

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. kappa-Opioid agonists possess several actions that are opposite to micro -opioid agonists. We proposed to investigate the role of kappa-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 degrees 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 micro g)-induced scratching while maintaining or enhancing i.t. morphine-induced 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 agonist-induced pruritus.

Butorphanol prevents morphine-induced pruritus without increasing pain and other side effects: a systematic review of randomized controlled trials

“…Currently, the mechanism underlying morphine-related pruritus remains uncertain, but morphine-induced pruritus is considered mediated by the l-opioid receptors 31 and the j-opioid receptors. 32,33 Accordingly, administration of butorphanol (a partial l-opioid receptor antagonist and j-opioid receptor agonist) with morphine (l-and j-receptor agonist) would be expected to maintain analgesia (l-and j-receptors) while reducing pruritus. 21 Butorphanol has been used to treat intractable pruritus based on its potential anti-pruritus effect, 5 but debate on the efficacy of prophylactic butorphanol on morphine-induced pruritus still exists.…”

Characterization of scratching responses in rats following centrally administered morphine or bombesin

“…bombesin-induced scratching (Gmerek and Cowan, 1984;Cowan and Gmerek, 1986), which indicates that kappaopioid agonists may be effective for treating refractory pruritus. As noted, kappa-opioid agonists have been shown to inhibit scratching behavior induced by morphine in monkeys (Ko et al, 2003). It will be worthwhile to determine whether kappa-opioid agonists can attenuate scratching produced by centrally administered bombesin in non-human primates.…”

κ-Opioid System in Uremic Pruritus

“…-Agonists have been shown to block the itching response of morphine through a central effect (13,21) while maintaining or enhancing morphine-induced antinociception. This anti-pruritic effect may be due to a direct effect in one or more areas of the brain and/or a positive feedback from the skin at the level of the spinal cord.…”