It is well established that
muscarinic cholinergic agonists produce antinociceptive effects in a number of
acute pain models. However, relatively little is known about the effects of
muscarinic receptor agonists in models which involve central sensitization in
pain pathways. The purpose of the present studies was to evaluate the effects of
vedaclidine, a
muscarinic receptor mixed agonist/antagonist across receptor subtypes, in models involving central sensitization.
Vedaclidine (0.3-10 mg/kg s.c.) produced dose-related antihyperalgesic effects in the
formalin test as well as a dose-related reversal of
capsaicin-induced
mechanical hyperalgesia in rats. In the
carrageenan test,
vedaclidine (0.1-30 mg/kg) produced a dose-related reversal of both mechanical and
thermal hyperalgesia that were antagonized by the
muscarinic receptor antagonist
scopolamine. In addition, the antihyperalgesic effects of
vedaclidine in the
carrageenan test were synergistic with the antihyperalgesic effects of the non-steroidal antiinflammatory
drug ketoprofen, as demonstrated by isobolographic analysis. The present studies demonstrate that
vedaclidine produces antihyperalgesic effects in models involving central sensitization, suggesting that
vedaclidine, and potentially other
muscarinic receptor agonists, may have clinical utility in the management of
pain states involving central sensitization, such as neuropathic and inflammatory
pain states.