The pathogenic form of the
cyclooxygenase (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
COX-2 inhibitor,
GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]
pyridazine, where X denotes the free base], is as effective as
rofecoxib and
celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for
rofecoxib and 6.6 mg/kg p.o. for
celecoxib. However, in contrast to
celecoxib (5 mg/kg p.o. b.i.d.) and
rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect,
GW406381X (5 mg/kg p.o. b.i.d.) 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 sensitization, when given intrathecally (ED(50) = 0.07 mug) 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 central nervous system penetration,
enzyme kinetics, and potency. The novel finding of effectiveness of
GW406381X in these models of
neuropathic pain/central sensitization, in addition to activity in inflammatory
pain models and together with its central efficacy, suggests dual activity of
GW406381X compared with
celecoxib and
rofecoxib, which may translate into greater efficacy in a broader spectrum of
pain states in the clinic.