New morphine analogs produce peripheral antinociception within a certain dose range of their systemic administration

Erzsébet Lackó, P. Riba, Z. Giricz, A. Váradi, Laura Cornic, Mihály Balogh, Kornél Király, Kata Cseko, Shaaban A. Mousa, Sándor Hosztafi, Michael Schäfer, Z. Zádori, Z. Helyes, Péter Ferdinandy, S. Fürst, M. Al-Khrasani

Research output: Contribution to journalArticle

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Abstract

Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund's adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)-reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.

Original languageEnglish
Pages (from-to)171-181
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume359
Issue number1
DOIs
Publication statusPublished - Oct 1 2016

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Morphine
Pain
Opioid Analgesics
Visceral Pain
Gastrointestinal Transit
Injections
Freund's Adjuvant
Acetic Acid
Central Nervous System
14-O-methylmorphine-6-O-sulfate
morphine-6-O-sulfate
Lung
Brain
N-methylnaloxone

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

New morphine analogs produce peripheral antinociception within a certain dose range of their systemic administration. / Lackó, Erzsébet; Riba, P.; Giricz, Z.; Váradi, A.; Cornic, Laura; Balogh, Mihály; Király, Kornél; Cseko, Kata; Mousa, Shaaban A.; Hosztafi, Sándor; Schäfer, Michael; Zádori, Z.; Helyes, Z.; Ferdinandy, Péter; Fürst, S.; Al-Khrasani, M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 359, No. 1, 01.10.2016, p. 171-181.

Research output: Contribution to journalArticle

Lackó, Erzsébet ; Riba, P. ; Giricz, Z. ; Váradi, A. ; Cornic, Laura ; Balogh, Mihály ; Király, Kornél ; Cseko, Kata ; Mousa, Shaaban A. ; Hosztafi, Sándor ; Schäfer, Michael ; Zádori, Z. ; Helyes, Z. ; Ferdinandy, Péter ; Fürst, S. ; Al-Khrasani, M. / New morphine analogs produce peripheral antinociception within a certain dose range of their systemic administration. In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 359, No. 1. pp. 171-181.
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