Disability of Development of Tolerance to Morphine and U-50,488H, a Selective κ-Opioid Receptor Agonist, in Neuropathic Pain Model Mice

Abstract

Abstract. We examined the analgesic and anti-allodynic effects of morphine and U-50,488H (trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methanesulfonate salt), a selective k-opioid receptor agonist, and the development of tolerance to their effects in neuropathic pain model mice induced by sciatic nerve ligation (SNL). In the tail-pinch method, morphine at 10 mg / kg, s.c. produced a weak analgesic effect in SNL mice; however, U-50,488H at 5 mg / kg, s.c. produced an analgesic effect equipotent to that in normal mice. In contrast, morphine produced an adequate analgesic effect when given either intracerebroventricularly (i.c.v.) or intrathecally (i.t.), but U-50,488H only produced analgesia when given i.t. Repeated administration of morphine (either i.c.v. or i.t.) or U-50,488H (either s.c. or i.t.), did not induce tolerance to the effect. In the static allodynia test with an application of von Frey filaments, both compounds given s.c. suppressed the allodynic effect, but in the dynamic allodynia test involving lightly stroking the plantar surface with a cotton bud, only U-50,488H produced an anti-allodynic effect. Repeated administrations of both compounds did not develop tolerance to these anti-allodynic effects. Thus, U-50488H was found to be a highly effective at blocking hyperalgesia and allodynia in nerve injury, and these findings suggest that k-opioid receptor agonists are attractive pharmacological targets for the control of patients with neuropathic pain.

Pain-relieving effects of processed Aconiti tuber in CCI-neuropathic rats

“…Unlike morphine, the analgesic potency of U-50,488H was not decreased in SNL neuropathic mice, compared with normal mice; and, U-50,488H, but not morphine, significantly reduced dynamic tactile allodynia (Sounvoravong et al, 2004). The high effectiveness of U-50,488H in blocking hyperalgesia and allodynia in neuropathic mice suggests that kappa-opioid receptor agonists can be attractive pharmacological targets for the control of neuropathic pain (Sounvoravong et al, 2004).…”

“…Although sustained activation of kappa-opioid receptors may induce tolerance to kappa-opioid analgesia (Xu et al, 2004), another study did not find the development of tolerance to analgesic or anti-allodynic effects of U-50,488H, a kappa-opioid receptor agonist, in SNL neuropathic mice (Sounvoravong et al, 2004). Unlike morphine, the analgesic potency of U-50,488H was not decreased in SNL neuropathic mice, compared with normal mice; and, U-50,488H, but not morphine, significantly reduced dynamic tactile allodynia (Sounvoravong et al, 2004).…”

“…In this regard, kappa-opioid receptor agonists may have some advantages over mu-opioid receptor agonists, because they are generally devoid of problematic side effects, such as dependence, addiction, and respiratory depression (Horwell, 1988;Walsh et al, 2001). Further, a recent study suggested that selective kappa-opioid receptor agonists are more effective in relieving pain and allodynia, in a mouse model of neuropathic pain, compared with morphine (Sounvoravong et al, 2004).…”

“…Currently, Aconiti tuber, processed by autoclaving to minimize its toxicity, is used widely and safely for various clinical indications (Murayama et al, 1991;Ameri et al, 1998;Taki et al, 1998). Recent research has shown that the anti-nociceptive effect of processed Aconiti tuber is mediated by spinal kappa-opioid receptor mechanisms (Omiya et al, 1999;Suzuki et al, 1999), and therefore, it may be effective in relieving neuropathic pain, as other kappa-opioids (Sounvoravong et al, 2004). To date, however, pain-relieving effects of processed Aconiti tuber have not been evaluated in experimental or clinical neuropathic pain.…”

Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

“…The doses of morphine and SCH221510 were selected based on the previous studies in rodent pain models using NOP or MOP agonists (Hao et al, 1998;Sounvoravong et al, 2004;Obara et al, 2005). We hypothesized that for a compound with the ability to activate NOP and MOP receptors it may be ideal to use doses that were 3 to 10 times lower than those of SCH221510 and morphine.…”