title: Antihyperalgesic, Antiallodynic, and Antinociceptive Effects of Cebranopadol, a Novel Potent Nociceptin/Orphanin FQ and Opioid Receptor Agonist, after Peripheral and Central Administration in Rodent Models of Neuropathic Pain.
abstract: Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. In STZ-treated rats, cebranopadol (i.pl.) reduced mechanical hypersensitivity in the ipsilateral paw, but had no effect at the contralateral paw. In CCI rats, cebranopadol (i.pl.) showed antiallodynic activity at the ipsilateral paw. After administration to the contralateral paw, cebranopadol also showed ipsilateral antiallodynic activity, but with reduced potency and delayed onset. In diabetic mice, cebranopadol i.th. and i.c.v. decreased heat hyperalgesia with full efficacy and similar potency for both routes. Cebranopadol also produced significant antinociception in nondiabetic controls. Thus, cebranopadol exerts potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects after local/peripheral, spinal, and supraspinal administration. The contralateral effects after i.pl. administration were likely due to systemic redistribution. After central administration of cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.
authors.affiliation: Pharmacology and Biomarker Development, Grünenthal GmbH, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
authors.affiliation: Preclinical Drug Development, Grünenthal GmbH, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Linz
authors.affiliation: Preclinical Drug Development, Grünenthal GmbH, Aachen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Frosch
authors.affiliation: Pharmacology and Biomarker Development, Grünenthal GmbH, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D018847:Opioid Peptides / Q000819:agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists; D013141:Spiro Compounds / Q000494:pharmacology*; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D007211:Indoles; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000097629:Nociceptin; C000589289:6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro(cyclohexane-1,1'(3'H)-pyrano(3,4-b)indol)-4-amine
keywords: acute pain; allodynia; hyperalgesia; neuropathic pain; nociceptin/orphanin FQ