New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration

Lackó, Erzsébet and Riba, Pál and Giricz, Zoltán and Váradi, András and Cornic, Laura and Balogh, Mihaly and Király, Kornél and Csekő, Kata and Mousa, Shabban and Hosztafi, Sándor and Schäfer, Michael and Zádori, Zoltán S. and Helyes, Zsuzsanna and Ferdinandy, Péter and Fürst, Zsuzsanna and Al-Khrasani, Mahmoud (2016) New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration. The Journal of Pharmacology and Experimental Therapeutics, 359 (1). pp. 171-181. ISSN 0022-3565, ESSN: 1521-010

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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.

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