Kappa opioid analgesia is dependent on serotonergic mechanisms.
The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays, as did reserpine pretreatment. Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. Likewise, it did not alter the development of U-50,488H tolerance. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D011985:Receptors, Serotonin / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology
D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D011985:Receptors, Serotonin; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D012110:Reserpine; D006916:5-Hydroxytryptophan