Effects of Butorphanol on Morphine-induced Itch and Analgesia in Primates

Abstract

Butorphanol is effective in attenuating systemic or spinal morphine-induced itch without reducing morphine analgesia. This study provides functional evidence that both partial MOR and KOR agonist actions contribute to the effectiveness of butorphanol as an antipruritic in primates.

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

“…However, as previously demonstrated, intrathecal morphine simultaneously produces both scratching and antinociception in monkeys, but not in rodents (Ko and Naughton, 2000;Ko et al, 2003a;Lee et al, 2003). The present study of KOR agonists as antipruritics in primates further extends the therapeutic application of KOR agonists under the context of spinal opioid analgesia (Ko et al, 2003a;Lee et al, 2007; the present study). More importantly, a recent study demonstrated that there are two separate populations of spinothalamic tract neurons responding to histamine versus nonhistaminergic pruritogenic agent, cowhage, in monkeys (Davidson et al, 2007).…”

“…Nalfurafine (0.1-1 g/kg), bremazocine (0.1-1 g/kg), or GR 89696 (0.01-0.1 g/kg) was administered intramuscularly 45 min after 0.03 mg of intrathecal morphine. This dose of intrathecal morphine was selected based on previous studies showing that it produced maximal scratching responses and antinociception, and it could be used to detect whether the test compound could attenuate scratching without interfering intrathecal morphine-induced antinociception (Ko and Naughton, 2000;Lee et al, 2007). In a separate experiment, the tail-withdrawal latencies were measured at the same time points (i.e., measurement per half hour) in the same monkeys that were given effective antiscratching doses of KOR agonists 45 min after intrathecal morphine.…”

“…More importantly, the KOR antagonist study revealed that antiscratching effects of both nalfurafine and U-50488H could be blocked completely by nor-BNI pretreatment. For comparison, a recent study has demonstrated that nor-BNI can only partially block antiscratching effects of butorphanol because this drug has dual actions (i.e., partial agonist action at both KOR and -opioid receptors) as an antipruritic (Lee et al, 2007). If nalfurafine's -opioid antagonist or partial agonist effect significantly contributes to its antiscratching effects, it is expected that pretreatment with nor-BNI could only partially reverse nalfurafine's antiscratching effects.…”

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

“…Interestingly, such unique effects of intrathecal morphine in humans [2,31] can be modeled in monkeys, but not in rodents, as a single dose of morphine produced both antinociception and itch/scratching responses simultaneously in monkeys [17,20,24]. For studying opioid analgesics in vivo, the scratching response can be used as a selective behavioral endpoint corresponding to activation of MOP [18,25]. Given that pruritus is a long standing side effect associated with the use of intrathecal morphine [7,8], lack of scratching responses by intrathecal UFP-112 in monkeys strongly suggests that UPF-112 has the therapeutic potential as a spinal analgesic.…”

“…30,39 On the other hand, increased scratching is also considered as a behavioral response to itch sensation in rodents receiving pruritogenic agents. 16,23,25 Whether scratching behavior is pain-related or itch-related depends on the context. Several factors such as administration routes and species differences may also contribute to different results or interpretations in the behavioral pharmacology of itch.…”