title: Bifunctional opioid/nociceptin hybrid KGNOP1 effectively attenuates pain-related behaviour in a rat model of neuropathy.
abstract: A bifunctional peptide containing an opioid and nociceptin receptor-binding pharmacophore, H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2 (KGNOP1), was tested for its analgesic properties when administered intrathecally in naïve and chronic constriction injury (CCI)-exposed rats with neuropathy-like symptoms. KGNOP1 significantly increased the acute pain threshold, as measured by the tail-flick test, and also increased the threshold of a painful reaction to mechanical and thermal stimuli in CCI-exposed rats. Both of the effects could be blocked by pre-administration of [Nphe1]-Nociceptin (1-13)-NH2(NPhe) or naloxone, antagonists for nociceptin and opioid receptors, respectively. This led us to conclude that KGNOP1 acts as a dual opioid and nociceptin receptor agonist in vivo. The analgesic effect of KGNOP1 proved to be more powerful than clinical drugs such as morphine and buprenorphine. Repeated daily intrathecal injections of KGNOP1 led to the development of analgesic tolerance, with the antiallodynic action being completely abolished on day 6. Nevertheless, the development of tolerance to the antihyperalgesic effect was delayed in comparison to morphine, which lost its efficacy as measured by the cold plate test after 3days of daily intrathecal administration, whereas KGNOP1 was efficient up to day 6. A single intrathecal injection of morphine to KGNOP1-tolerant rats did not raise the pain threshold in any of the behavioural tests; in contrast, a single intrathecal dose of KGNOP1 significantly suppressed allodynia and hyperalgesia in morphine-tolerant rats.
authors.affiliation: Institute of Pharmacology, Department of Pain Pharmacology, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Starnowska
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Guillemyn
authors.affiliation: Institute of Pharmacology, Department of Pain Pharmacology, Krakow, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Institute of Pharmacology, Department of Pain Pharmacology, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: sballet@vub.ac.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.affiliation: Institute of Pharmacology, Department of Pain Pharmacology, Krakow, Poland. Electronic address: barbara.przewlocka@gmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
mesh_terms: D059787:Acute Pain / Q000188:drug therapy*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal; D002047:Buprenorphine / Q000627:therapeutic use; D004195:Disease Models, Animal; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D009020:Morphine / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D018847:Opioid Peptides; D010147:Pain Measurement; D010812:Physical Stimulation; D017208:Rats, Wistar; D000097629:Nociceptin
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine; D009020:Morphine; D009842:Oligopeptides; D018847:Opioid Peptides; D000097629:Nociceptin; C000624685:KGNOP1 peptide
keywords: Acute pain; Hybrid peptides; Neuropathic pain; Nociceptin receptor; Opioid receptors; Tolerance