title: Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity.
abstract: Oxaliplatin and paclitaxel are considered central components in the treatment of colorectal and breast cancer, respectively. The development of neuropathy during chronic treatment represents the major dose-limiting side effect that leads to discontinuation or interruption of therapies. The management of neuropathy is a challenge to individuate innovative therapeutic strategies based on new targets and correct routes of administration. We evaluated the hypersensitivity reliever effect of different opioid receptor agonists in rat models of oxaliplatin and paclitaxel-induced neuropathy. Compounds were spinally infused by intrathecal catheter. In oxaliplatin-treated rats, 0.3 nmol morphine induced the reversion of the mechanical hypersensitivity (Paw-pressure test), nociceptin/orphanin FQ (N/OFQ; 0.3-3 nmol) significantly increased the pain threshold without reaching the values of the control animals. The N/OFQ peptide (NOP) receptor full agonist UFP-112 reverted pain threshold alterations at lower dosage (0.1 nmol) vs morphine and N/OFQ, the partial agonist UFP-113 (0.1-1 nmol) was similar to N/OFQ. The higher efficacy of morphine vs N/OFQ was highlighted also in paclitaxel-treated rats. The mechanical hypersensitivity was fully reverted by 0.1 nmol UFP-112 and UFP-113. In conclusion, intrathecal μ opioid peptide (MOP) and NOP receptor agonists relieved chemotherapy-induced neuropathic pain. The synthetic peptides showed valuable potency and efficacy suggesting the NOP system as an exploitable target.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy. Electronic address: lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D018847:Opioid Peptides / Q000627:therapeutic use*; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D018847:Opioid Peptides; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C525846:nociceptin-amide, Nphe(1)-(pF)Phe(4)-Aib(7)-Arg(14)-Lys(15)-; C000722285:Oprl1 protein, rat
keywords: Chemotherapy-induced neuropathic pain; Intrathecal catheterization; NOP agonists; Opioids; Oxaliplatin; Paclitaxel