Rationale: Formalin-induced pain is reduced in sigma-1 (sigma1) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for sigma1 receptors, may modulate formalin-induced pain.
Results: Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03-1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25-8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4-128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (-)sulpiride (200 mg/kg), which have no affinity for sigma1 receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol>metabolite II>metabolite I>>metabolite III= (-)sulpiride=inactive] correlated with their affinity for sigma1 receptors, but not with their affinity for sigma2 or dopamine D2 receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test.
Conclusion: These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with sigma1 receptors.