PT  - JOURNAL ARTICLE
AU  - Garth T. Whiteside
AU  - James E. Harrison
AU  - Michelle S. Pearson
AU  - Zhengming Chen
AU  - Yakov Rotshteyn
AU  - Paul I. Turchin
AU  - James D. Pomonis
AU  - Lilly Mark
AU  - Katharine Walker
AU  - Kevin C. Broglé
TI  - DiPOA ([8-(3,3-Diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic Acid), a Novel, Systemically Available, and Peripherally Restricted Mu Opioid Agonist with Antihyperalgesic Activity: II. In Vivo Pharmacological Characterization in the Rat
AID  - 10.1124/jpet.103.063560
DP  - 2004 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 793--799
VI  - 310
IP  - 2
4099  - http://jpet.aspetjournals.org/content/310/2/793.short
4100  - http://jpet.aspetjournals.org/content/310/2/793.full
SO  - J Pharmacol Exp Ther2004 Aug 01; 310
AB  - Mu opioid receptors are expressed throughout the central and peripheral nervous systems. Peripheral inflammation leads to an increase in mu receptor present on the peripheral terminals of primary sensory neurons. Activation of peripheral mu receptors produces potent antihyperalgesic effects in both humans and animals. Here, we describe the in vivo pharmacological properties of the structurally novel, highly potent, systemically available yet peripherally restricted mu opioid agonist, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA). DiPOA administered i.p. produced naltrexone-sensitive, dose-dependent reversal of Freund's complete adjuvant-induced inflammatory mechanical hyperalgesia (1-10 mg/kg). Maximum percent reversal (67%) was seen 1 h postadministration at 10 mg/kg (the highest dose studied). DiPOA also proved antihyperalgesic in a model of postsurgical pain with a maximum percent reversal of 85% 1 h postadministration at 30 mg/kg i.p. (the highest dose studied). DiPOA administered i.p. had no effect in the tail flick assay of acute pain (0.1-10 mg/kg), produced no ataxia as measured by latency to fall from an accelerating rotarod (3-30 mg/kg), and was not antihyperalgesic in the Seltzer model of neuropathic pain (1-10 mg/kg). This is the first report of a peripherally restricted, small-molecule mu opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically.