Bifunctional opioid/nociceptin hybrid KGNOP1 effectively attenuates pain-related behaviour in a rat model of neuropathy.
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.
['Starnowska|Joanna|J|', 'Guillemyn|Karel|K|', 'Makuch|Wioletta|W|', 'Mika|Joanna|J|', 'Ballet|Steven|S|', 'Przewlocka|Barbara|B|']
D059787:Acute Pain D000701:Analgesics, Opioid D000818:Animals D001522:Behavior, Animal D002047:Buprenorphine D004195:Disease Models, Animal D006358:Hot Temperature D006930:Hyperalgesia D009020:Morphine D009437:Neuralgia D009842:Oligopeptides D018847:Opioid Peptides D010147:Pain Measurement D010812:Physical Stimulation D017208:Rats, Wistar
Acute pain Opioid receptors Nociceptin receptor Tolerance Hybrid peptides Neuropathic pain