The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats
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Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253–1012 nmol/kg) and morphine (3884–31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.
KeywordsAntinociception Opioids 14-O-methylmorphine-6-O-sulfate Peripheral CNS
The authors thank Semmelweis University Doctoral School (EFOP-3.6.3.-VEKOP-16-2017-00009) and Richter Gedeon Plc., Budapest, Hungary (Centenáriumi Alapítvány Research Grant) awarded to Dr. Mihály Balogh; ÚNKP-17-4 New National Excellence Program of the Ministry of Human Capacities (awarded to Dr. Zoltán S. Zádori).
- 3.Khalefa BI, Mousa SA, Shaqura M et al (2013) Peripheral antinociceptive efficacy and potency of a novel opioid compound 14-O-MeM6SU in comparison to known peptide and non-peptide opioid agonists in a rat model of inflammatory pain. Eur J Pharmacol 713:54–57. https://doi.org/10.1016/j.ejphar.2013.04.043 CrossRefPubMedGoogle Scholar
- 5.Fürst S, Riba P, Friedmann T et al (2005) Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J Pharmacol Exp Ther 312:609–618. https://doi.org/10.1124/jpet.104.075176 CrossRefPubMedGoogle Scholar
- 11.Coderre TJ, Yashpal K (1994) Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model. Eur J Neurosci 6:1328–1334. https://doi.org/10.1111/j.1460-9568.1994.tb00323.x CrossRefPubMedGoogle Scholar
- 15.Bianchi G, Fiocchi R, Tavani A, Manara L (1982) Quaternary narcotic antagonists’ relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. Life Sci 30:1875–1883. https://doi.org/10.1016/0024-3205(82)90467-2 CrossRefPubMedGoogle Scholar