Previous studies have suggested a possible pain-modulatory role for histamine H(3) receptors, but the localization of these receptors and nature of this modulation is not clear. In order to explore the role of spinal histamine H(3) receptors in the inhibition of nociception, the effects of systemically (subcutaneous, s.c.) and intrathecally (i.t.) administered histamine H(3) receptor agonists were studied in rats and mice. Immepip (5 mg/kg, s.c.) produced robust antinociception in rats on a mechanical (tail pinch) test but did not alter nociceptive responses on a thermal (tail flick) test. In contrast, this treatment in mice (immepip, 5 and 30 mg/kg, s.c.) did not change either mechanically or thermally evoked nociceptive responses. When administered directly into the spinal subarachnoid space, immepip (15-50 microg, i.t.) and R-alpha-methylhistamine (50 microg, i.t.) had no effect in rats on the tail flick and hot plate tests, but produced a dose- and time-dependent inhibition (90-100%) of nociceptive responses on the tail pinch test. This attenuation was blocked by administration of thioperamide (10 mg/kg, s.c.), a histamine H(3) receptor antagonist. Intrathecally administered thioperamide also reversed antinociceptive responses induced by systemically administered immepip, which demonstrates a spinal site of action for the histamine H(3) receptor agonist. In addition, intrathecally administered immepip (25 microg) produced maximal antinociception on the tail pinch test in wild type, but not in histamine H(3) receptor knockout (H(3)KO) mice. These findings demonstrate an antinociceptive role for spinal histamine H(3) receptors. Further studies are needed to confirm the existence of modality-specific (i.e. mechanical vs. thermal) inhibition of nociception by these receptors, and to assess the efficacy of spinally delivered histamine H(3) receptor agonists for the treatment for pain.