title: Effects of repeated dosing with mechanistically distinct antinociceptive ligands in a rat model of neuropathic spinal cord injury pain.
abstract: A lack of efficacy of some analgesic drugs has been previously described in rats with neuropathic spinal cord injury (SCI) pain. It has been suggested that repeated dosing in these animals over time may eventually lead to efficacy. However, it is also possible that efficacy may diminish over time with repeated dosing. This study evaluated the efficacy of various drugs upon repeated dosing over time in a rat model of SCI pain. Four weeks following an acute spinal cord compression at the mid-thoracic level, rats developed decreased hind paw withdrawal threshold, suggestive of below level neuropathic hypersensitivity. Either cannabinoid (CB) receptor agonist CP 55,940, the anticonvulsant carbamazepine or gabapentin, the antidepressant amitriptyline or vehicle was administered over a period of 7 days. Neither carbamazepine nor amitriptyline demonstrated efficacy either after a single or repeated dosing. Beginning with a 50% efficacious dose of gabapentin, the effect of gabapentin in SCI rats neither increased nor decreased over the treatment period. The antinociceptive effect of CP 55,940 was maintained for the entire treatment period, which was mediated by CB1 but not CB2 receptors. The current data suggest that sustained antinociception can be obtained with some drugs in rats with neuropathic SCI pain. Furthermore, the current data do not substantiate the notion that repeated treatment with initially ineffective drugs will eventually lead to efficacy; treatments that are not acutely effective are unlikely to demonstrate clinical efficacy.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine Miami, Florida, 33136.
authors.forename: Aldric T
authors.initials: AT
authors.lastname: Hama
authors.affiliation: Ironwood Pharmaceuticals, Inc. Cambridge, Massachusetts, 02142.
authors.forename: James P
authors.initials: JP
authors.lastname: Pearson
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine Miami, Florida, 33136.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sagen
keywords: Acute drug challenge; amitriptyline; below level neuropathic pain; cannabinoid receptor agonist; carbamazepine; repeated drug dosing