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Interaction between the μ‐agonist dermorphin and the δ‐agonist [D‐Ala 2 , Glu 4 ]deltorphin in supraspinal antinociception and δ‐opioid receptor binding
Author(s) -
Negri L.,
Improta G.,
Lattanzi R.,
Potenza R.L.,
Luchetti F.,
Melchiorri P.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15947.x
Subject(s) - naltrindole , dermorphin , agonist , chemistry , opioid receptor , medicine , (+) naloxone , endocrinology , opioid , μ opioid receptor , receptor , enkephalin , damgo , opioid peptide , pharmacology , biochemistry , biology
1 In rats, the interaction between the μ‐opioid agonist dermorphin and the δ‐opioid agonist [D‐Ala 2 , Glu 4 ]deltorphin was studied in binding experiments to δ‐opioid receptors and in the antinociceptive test to radiant heat. 2 When injected i.c.v., doses of [D‐Ala 2 , Glu 4 ]deltorphin higher than 20 nmol produced antinociception in the rat tail‐flick test to radiant heat. Lower doses were inactive. None of the doses tested elicited the maximum achievable response. This partial antinociception was accomplished with an in vivo occupancy of more than 97% of brain δ‐opioid receptors and of 17% of μ‐opioid receptors. Naloxone (0.1 mg kg −1 , s.c), and naloxonazine (10 mg kg −1 , i.v., 24 h before), but not the selective δ‐opioid antagonist naltrindole, antagonized the antinociception. 3 In vitro competitive inhibition studies in rat brain membranes showed that [D‐Ala 2 , Glu 4 ]deltorphin displaced [ 3 H]‐naltrindole from two δ‐binding sites of high and low affinity. The addition of 100 μ m Gpp[NH]p produced a three fold increase in the [D‐Ala 2 , Glu 4 ]deltorphin K i value for both binding sites. The addition of 10 nM dermorphin increased the K i value of the δ‐agonist for the high affinity site five times. When Gpp[NH]p was added to the incubation medium together with 10 nM dermorphin, the high affinity K i of the δ‐agonist increased 15 times. 4 Co‐administration into the rat brain ventricles of subanalgesic doses of dermorphin and [D‐Ala 2 , Glu 4 ]deltorphin resulted in synergistic antinociceptive responses. 5 Pretreatment with naloxone or with the non‐equilibrium μ‐antagonists naloxonazine and β∼ funaltrexamine completely abolished the antinociceptive response of the μ‐δ agonist combinations. 6 Pretreatment with the δ‐opioid antagonists naltrindole and DALCE reduced the antinociceptive response of the dermorphin‐[D‐Ala 2 , Glu 4 ]deltorphin combinations to a value near that observed after the μ‐agonist alone. At the dosage used, naltrindole occupied more than 98% of brain δ‐opioid receptors without affecting μ‐opioid‐receptors. 7 These data suggest that in the rat tail‐flick test to radiant heat, μ‐ and δ‐opioid agonists co‐operate positively in evoking an antinociceptive response. Although interactions between different opioid pathways cannot be excluded, in vitro binding results indicate that this co‐operative antinociception is probably mediated by co‐activation of the δ‐opioid receptors at the cellular level by the μ‐ and δ‐agonist.