6--guanidinonaltrindole and Pain

During the past decade, substantial evidence has documented that opioid receptor heterodimers form in cell lines expressing one or more opioid receptors. More recent studies have begun to investigate whether heterodimer formation also occurs in vivo.. We have used opioid receptor knockout mice to determine whether the in vivo intrathecal (i.t.) pharmacological potency of delta, kappa, and bivalent kappa/delta ligands is altered in the absence of the KOR-1 and/or DOR-1 genes.. We observe that both NorBNI (a kappa antagonist) and KDN-21 (a kappa/delta bivalent antagonist) specifically inhibit DPDPE but not deltorphin II i.t potency in wild-type mice but that following mutation of KOR-1, the ability of either compound to reduce DPDPE potency is lost. In contrast, knockout of KOR-1 unexpectedly slightly reduces the potency of deltorphin II (delta2) but not DPDPE (delta1). Finally, two compounds with kappa agonist activity, 6'-GNTI (a putative kappa/delta heterodimer selective agonist) and KDAN-18 (kappa agonist/delta antagonist bivalent ligand) show reduced potency in DOR-1 KO mice.. These results show, genetically, that bivalent ligands with kappa agonist activity require delta receptors for maximal potency in vivo, which is consistent with the presence of opioid heterodimer/oligomer complexes in vivo, and also highlight the complexity of delta drug action even when complementary pharmacologic and genetic approaches are used.

Topics: Amides; Animals; Dose-Response Relationship, Drug; Enkephalin, D-Penicillamine (2,5)-; Guanidines; Ligands; Male; Mice; Mice, Knockout; Naltrexone; Oligopeptides; Pain; Protein Multimerization; Receptors, Opioid, delta; Receptors, Opioid, kappa

The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.

Topics: Analgesics; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Female; Formaldehyde; Guanidines; Indoles; Melatonin; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Postural Balance; Rats; Rats, Wistar; Receptor, Melatonin, MT2