title: Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain.
abstract: Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Devki D
authors: DD
authors: Sukhtankar
authors: Nurulain T
authors: NT
authors: Zaveri
authors: Stephen M
authors: SM
authors: Husbands
authors: Mei-Chuan
authors: MC
authors: Ko
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000775:Anesthesia, Spinal / Q000009:adverse effects / Q000379:methods; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002047:Buprenorphine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D043803:Phenalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: C583123:1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)indolin-2-one; C557645:2-(N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl)-3,3-dimethylpentan-2-ol; C530605:8-(bis(2-methylphenyl)methyl)-3-phenyl-8-azabicyclo(3.2.1)octan-3-ol; D000701:Analgesics, Opioid; D053961:Azabicyclo Compounds; D007211:Indoles; D008024:Ligands; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; C404943:Oprm protein, mouse; D043803:Phenalenes; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse
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