Thienorphine induces antinociception without dependence through activation of κ- and δ-, and partial activation of μ- opioid receptor
| Autor: | Ruibin Su, Yulei Li, Yixin Zhang, Peilan Zhou, Zehui Gong, Ming Chen, Zheng Yong |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Nociception 0301 basic medicine Formalin Test μ receptor medicine.drug_class Hydrochloride Receptors Opioid mu Pain Pharmacology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Opioid Agonist Opioid receptor Cell Line Tumor Receptors Opioid delta Cyclic AMP medicine Animals Humans Rats Wistar Hot plate test Molecular Biology Mice Knockout Neurons Receptors Opioid kappa General Neuroscience Brain Thienorphine Buprenorphine Rats Analgesics Opioid 030104 developmental biology Opioid chemistry Female Neurology (clinical) 030217 neurology & neurosurgery Developmental Biology medicine.drug |
| Zdroj: | Brain Research. 1748:147083 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/j.brainres.2020.147083 |
| Popis: | Thienorphine hydrochloride is a new anti-relapse drug for opioid abusers that is currently in phase II clinical trial. In the present study, the antinociception, dependence, and signal transduction induced by thienorphine were examined. Thienorphine showed a potent antinociception effect in acetic acid-induced writhing test and formalin test. In the hot plate test and tail-flick test, thienorphine presented the typical partial opioid agonist character with a ceiling dose-response curve in addition to a bell-shaped curve. The hot plate test revealed that thienorphine induced approximately 50% of antinociception in μ receptor knockout (μ-KO) mice compared to wild-type controls (P 0.05). The κ, δ selective antagonist nor-binaltorphimine (nor-BNI), and naltrindole decreased approximately 50-60% of theinorphine antinociception in μ-KO mice, respectively. The ORL1 receptor-selective antagonist J113397 did not affect theinorphine antinociception in μ-KO mice. Chronic treatment with thienorphine (1.5 mg/kg) induced some tolerance that was lower compared to buprenorphine or morphine addition. In contrast to buprenorphine or morphine, thienorphine did not lead to psychological dependence by conditioned place preference (CPP). The maximum inhibition of thienorphine on protein kinase A (PKA) activity was about 36%, 100%, 100%, and 12% in CHO-μ/κ/δ/ORL1-PKAcatEGFP cells, respectively. Similar results were observed in cyclic adenosine monophosphate (cAMP) accumulation inhibited by thienorphine in cells. Thienorphine significantly increased pERK1/2 in CHO-κ/δ-PKAcatEGFP cells. These results indicated that thienorphine induced analgesia through activation of κ- and δ-, partial activation of μ- opioid receptor without a bias between G-protein- and β-arrestin-mediated pathways. Thienorphine might be used for antinociception with minimal adverse effects. |
| Databáze: | OpenAIRE |
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