title: Mechanical hyperalgesia in rats with diabetic polyneuropathy is selectively inhibited by local peripheral nociceptin/orphanin FQ receptor and µ-opioid receptor agonism.
abstract: Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1-71.4nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1±15.4% maximal possible effect (MPE) at the dose of 23.8nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8-257.8nmol/animal in a similar efficacy range with a maximal efficacy of 76.0±12.1% MPE at the dose of 257.8nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.
authors.affiliation: Global Preclinical Research and Development, Department of Pain Pharmacology (KS, TC, TMT), Global Early Clinical Development, Department of Translational Science (WS), Zieglerstrasse 6, 52078 Aachen, Germany. Electronic address: Klaus.Schiene@grunenthal.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schiene
authors.affiliation: Global Preclinical Research and Development, Department of Pain Pharmacology (KS, TC, TMT), Global Early Clinical Development, Department of Translational Science (WS), Zieglerstrasse 6, 52078 Aachen, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
authors.affiliation: Global Preclinical Research and Development, Department of Pain Pharmacology (KS, TC, TMT), Global Early Clinical Development, Department of Translational Science (WS), Zieglerstrasse 6, 52078 Aachen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schröder
authors.affiliation: Global Preclinical Research and Development, Department of Pain Pharmacology (KS, TC, TMT), Global Early Clinical Development, Department of Translational Science (WS), Zieglerstrasse 6, 52078 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy*; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009270:Naloxone / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000094942:Nociceptin Receptor
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D007093:Imidazoles; D009020:Morphine; D009270:Naloxone; D010880:Piperidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C121726:8-acenaphthen-1-yl-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one; C402921:J 113397; C000722285:Oprl1 protein, rat
keywords: Diabetic polyneuropathic pain; J-113397 (PubChem CID: 5311194); Morphine (PubChem CID: 5288826); Naloxone (PubChem CID: 5284596); Nociceptin/orphanin FQ (PubChem CID: 16131448); Ro65-6570 (=compound 1a; Rover et al., 2000); µ-opioid