Rationale: We evaluated the effects of haloperidol and its metabolites on capsaicin-induced mechanical hypersensitivity (allodynia) and on nociceptive pain induced by punctate mechanical stimuli in mice.
Results: Subcutaneous administration of haloperidol or its metabolites I or II (reduced haloperidol) dose-dependently reversed capsaicin-induced (1 microg, intraplantar) mechanical hypersensitivity of the hind paw (stimulated with a nonpainful, 0.5-g force, punctate stimulus). The order of potency of these drugs to induce antiallodynic effects was the order of their affinity for brain sigma-1 (sigma(1)) receptor ([(3)H](+)-pentazocine-labeled). Antiallodynic activity of haloperidol and its metabolites was dose-dependently prevented by the selective sigma(1) receptor agonist PRE-084, but not by naloxone. These results suggest the involvement of sigma(1) receptors, but discard any role of the endogenous opioid system, on the antiallodynic effects. Dopamine receptor antagonism also appears unlikely to be involved in these effects, since the D(2)/D(3) receptor antagonist (-)-sulpiride, which had no affinity for sigma(1) receptors, showed no antiallodynic effect. None of these drugs modified hind-paw withdrawal after a painful (4 g force) punctate mechanical stimulus in noncapsaicin-sensitized animals. As expected, the control drug gabapentin showed antiallodynic but not antinociceptive activity, whereas clonidine exhibited both activities and rofecoxib, used as negative control, showed neither.
Conclusion: These results show that haloperidol and its metabolites I and II produce antiallodynic but not antinociceptive effects against punctate mechanical stimuli and suggest that their antiallodynic effect may be due to blockade of sigma(1) receptors but not to dopamine receptor antagonism.