The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats

M Balogh, ZS Zádori, B Lázár, D Karádi, S László, SA Mousa, S Hosztafi, F Zádor, P Riba, M Schäfer, S Fürst, M Al-Khrasani*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)


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 sys-
temic 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.
Original languageEnglish
Pages (from-to)1250-1257
Number of pages8
Publication statusPublished - May-2018
Externally publishedYes

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