The
analgesic effect of
intrathecal injection of
epibatidine,
clonidine and
neostigmine, compounds that elevate ACh, was examined in the
formalin test, a model of post-injury central sensitization in the rat. The compounds were injected alone and in combination.
Intrathecal injection of
epibatidine alone did not alter
pain behaviors, compared to vehicle-treated rats.
Intrathecal injection of
clonidine dose-dependently reduced tonic
pain behaviors (ED(50)+/-95% confidence limits=6.7+/-4.8 microg). The combination of
clonidine and
epibatidine (C:E), in the ratio of 26:1, dose-dependently reduced tonic
pain behaviors; and the ED(50) of C:E was 1.1+/-0.98 microg a significant 6-fold leftward shift of the dose response curve, compared with
clonidine alone. The antinociceptive effect of C:E (26:1) was attenuated by pre-treatment with the nAChR antagonist
mecamylamine.
Neostigmine dose-dependently reduced tonic
pain behaviors (ED(50)=1.5+/-1.3 microg). The combination of
neostigmine and
epibatidine, in a ratio of 8:1, significantly shifted the dose response curve 4-fold to the left (ED(50)=0.4+/-0.3 microg). The effect is mediated in part by the activation of the nAChR and possibly by the enhanced release of ACh. These data demonstrate significant enhancement of the antinociceptive effects of spinally delivered
analgesics by a nAChR agonist, suggesting that this class of compounds may have utility as adjuvants when combined with conventional
therapeutics.