Received for publication September 17, 2004.
Revised November 17, 2004.
Accepted for publication November 23, 2004.

The cyclo-oxygenase 2 inhibitor, GW406381 is effective in animal models of neuropathic pain and central sensitisation

Abstract

The pathogenic form of the cyclo-oxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual acting cyclo-oxygenase 2 (COX-2) inhibitor, GW406381X, is as effective as rofecoxib and celecoxib in the rat established FCA model with an ED50 of 1.5mg/kg po compared to 1.0 mg/kg po for rofecoxib and 6.6mg/kg po for celecoxib. However, in contrast to celecoxib (5mg/kg po bid) and rofecoxib (5mg/kg po bid), which were without significant effect, GW406381X (5mg/kg po bid) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitisation, when given intrathecally (ED50=0.07ug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including CNS penetration, enzyme kinetics and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitisation, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared to celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.

Key words: COX-2, Central sensitisation, Cyclo-oxygenase, Inflammatory pain, Neuropathic pain, Rat