title: A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain.
abstract: The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition.
authors.affiliation: InterVivo Solutions Inc., 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Lau
authors.forename: C
authors.initials: C
authors.lastname: Dykstra
authors.forename: S
authors.initials: S
authors.lastname: Thevarkunnel
authors.forename: L B
authors.initials: LB
authors.lastname: Silenieks
authors.forename: I A M
authors.initials: IA
authors.lastname: de Lannoy
authors.forename: D K H
authors.initials: DK
authors.lastname: Lee
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005684:Gait / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000188:drug therapy; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D000069583:Pregabalin; D051381:Rats; D045442:Rotarod Performance Test; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002220:Carbamazepine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
keywords: Efficacy; Exposure; Pharmacokinetic; Translation