Premium
Agonist activity of naloxone benzoylhydrazone at recombinant and native opioid receptors
Author(s) -
Olianas Maria C,
Concas Danilo,
Onali Pierluigi
Publication year - 2006
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 - 10.1038/sj.bjp.0706601
Subject(s) - naltrindole , gtpgammas , agonist , damgo , chemistry , nociceptin receptor , opioid receptor , (+) naloxone , opioid , medicine , endocrinology , partial agonist , receptor , pharmacology , opioid peptide , biology , biochemistry
In the present study, we examined the pharmacological activity of the putative κ 3 ‐opioid receptor agonist naloxone benzoylhydrazone (NalBzoH) at recombinant human opioid receptors individually expressed in Chinese hamster ovary (CHO) cells and native opioid receptors present in rat striatum. At the μ ‐opioid receptor (MOR), NalBzoH stimulated guanosine‐5′‐ O ‐(3‐[ 35 S]thio)triphosphate ([ 35 S]GTP γ S) binding (pEC 50 =8.59) and inhibited cyclic AMP accumulation (pEC 50 =8.74) with maximal effects ( E max ) corresponding to 55 and 65% of those obtained with the MOR agonist DAMGO, respectively. The MOR antagonist CTAP blocked the stimulatory effects of NalBzoH and DAMGO with similar potencies. At the κ ‐opioid receptor (KOR), NalBzoH stimulated [ 35 S]GTP γ S binding (pEC 50 =9.70) and inhibited cyclic AMP formation (pEC 50 =9.45) as effectively as the selective KOR agonist (−)‐U‐50,488. The NalBzoH effect was blocked by the KOR antagonist nor‐binaltorphimine (nor‐BNI) (p K i =10.30). In CHO cells expressing the δ ‐opioid receptor (DOR), NalBzoH increased [ 35 S]GTP γ S binding (pEC 50 =8.49) and inhibited cyclic AMP formation (pEC 50 =8.61) almost as effectively as the DOR agonist DPDPE. Naltrindole (NTI), a selective DOR antagonist, completely blocked the response to NalBzoH (p K i of 10.40). In CHO cells expressing the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), NalBzoH failed to exert agonist effects and antagonized the agonist‐induced receptor activation. When compared to other opioid receptor ligands, NalBzoH showed an efficacy that was lower than that of morphine at MOR, but higher at KOR and DOR. In rat striatum, NalBzoH enhanced [ 35 S]GTP γ S binding and inhibited adenylyl cyclase activity. These effects were antagonized by either CTAP, nor‐BNI or NTI, each antagonist blocking a fraction of the NalBzoH response. These data demonstrate that NalBzoH displays agonist activity at MOR, DOR and KOR expressed either in a heterologous cell system or in a native environment.British Journal of Pharmacology (2006) 147 , 360–370. doi: 10.1038/sj.bjp.0706601