title: 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.affiliation: The Rockefeller University, Box 171, 1230 York Ave., New York, NY 10021, USA. butelme@mail.rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Harris
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000287:Administration, Topical; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D002211:Capsaicin; D004298:Dopamine / Q000031:analogs & derivatives*; D005260:Female; D005283:Fentanyl / Q000627:therapeutic use*; D008139:Loperamide / Q000627:therapeutic use*; D008253:Macaca mulatta; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects
chemical_list: D000700:Analgesics; D008139:Loperamide; D002211:Capsaicin; C488796:N-oleoyldopamine; D005283:Fentanyl; D004298:Dopamine