Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates.

Abstract

Capsaicin produces thermal allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1-1 mg/kg s.c.; a micro-opioid agonist that is peripherally selective after systemic administration), in preventing and reversing thermal allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay (n = 4; 38 degrees C and 42 degrees C; normally non-noxious thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating micro-agonist, fentanyl (0.0032-0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist ("endovanilloid"), N-oleoyldopamine (OLDA; 0.0013-0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced allodynia, whereas only fentanyl produced robust reversal of ongoing allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located micro-receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced allodynia. Up to the largest dose studied, loperamide was devoid of thermal antinociceptive effects at 48 degrees C (a noxious thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01-0.032 mg/kg) caused dose-dependent antinociception in this sensitive thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective micro-agonist after systemic administration, can prevent capsaicin-induced thermal allodynia in primates in vivo, in the absence of thermal antinociceptive effects.

• Authors: Eduardo R Butelman, Todd J Harris, Mary Jeanne Kreek
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 1 Pg. 155-63 (Oct 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15152028 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Analgesics
• Loperamide
• Capsaicin
• N-oleoyldopamine
• Fentanyl
• Dopamine

Topics

• Administration, Topical
• Analgesics (therapeutic use)
• Animals
• Capsaicin
• Dopamine (analogs & derivatives)
• Female
• Fentanyl (therapeutic use)
• Loperamide (therapeutic use)
• Macaca mulatta
• Pain (chemically induced, drug therapy, prevention & control)
• Pain Measurement (drug effects)