title: Comparison of antinociceptive actions of standard analgesics in attenuating capsaicin and nerve-injury-induced mechanical hypersensitivity.
abstract: Intradermal capsaicin injection produces immediate spontaneous pain behaviors, and a secondary mechanical hypersensitivity (SMH) that is employed in the clinic as a model potentially predictive of human neuropathic pain. Presently, we have characterized capsaicin-induced SMH in rats, and compared pharmacological actions of standard analgesics in this and two nerve injury models, the L5/L6 spinal nerve ligation (SNL) and sciatic nerve chronic constriction injury (CCI) models. Intraplantar capsaicin produced dose-related SMH (enhanced paw withdrawal response to von Frey monofilament stimulation at an area away from injection site) that lasted for over 4 h. While pretreatment with a potent selective transient receptor potential vanilloid receptor-1 (TRPV1) antagonist A-425619 (1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea) prevented development of acute nocifensive (flinching) behavior immediately following capsaicin injection (ED(50)=4.9 mg/kg), the compound failed to attenuate the SMH when administered 2 h following capsaicin (10 microg/10 microl). Additional standard analgesics were also tested 3 h following intraplantar capsaicin in the SMH model. Comparison of their potencies in attenuating mechanical hypersensitivity in capsaicin, SNL and CCI models revealed similar ED(50)s for morphine (2.3 mg/kg, 1.6 mg/kg and 3.2 mg/kg, respectively), gabapentin (33.1 mg/kg, 33.9 mg/kg and 26.3 mg/kg, respectively) and lamotrigine (9.1 mg/kg, 8.9 mg/kg and 15.5 mg/kg, respectively). Duloxetine produced 50-65% effect at the highest tested dose (50 mg/kg), whereas the highest tested doses of morphine (10 mg/kg), gabapentin (85.5 mg/kg) and lamotrigine (30 mg/kg) all produced >70% efficacy in capsaicin SMH, SNL and CCI models. In contrast, celecoxib and ibuprofen showed weak effects in all three models. All standard analgesics generally had weak efficacy in attenuating capsaicin-induced immediate acute flinching behavior when administered before capsaicin. These results provide further support to the suggestions that distinct pharmacological mechanisms underlie capsaicin-induced acute nocifensive and SMH behaviors, and certain neuronal mechanisms underlying neuropathic pain states are also contributory to capsaicin-induced SMH.
authors.affiliation: Abbott Laboratories, Neuroscience Research, GPRD R4N5 100 Abbott Park Road, Abbott Park, IL 60064, USA. shailen.joshi@abbott.com
authors.forename: S K
authors.initials: SK
authors.lastname: Joshi
authors.forename: G
authors.initials: G
authors.lastname: Hernandez
authors.forename: J P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: C Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: C
authors.initials: C
authors.lastname: Zhong
authors.forename: A
authors.initials: A
authors.lastname: Salyers
authors.forename: C T
authors.initials: CT
authors.lastname: Wismer
authors.forename: P
authors.initials: P
authors.lastname: Chandran
authors.forename: M W
authors.initials: MW
authors.lastname: Decker
authors.forename: P
authors.initials: P
authors.lastname: Honore
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007839:Functional Laterality; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014110:Touch
chemical_list: D000700:Analgesics; D009020:Morphine