Activation of spinal histamine H3 receptors inhibits mechanical nociception

Abstract 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 μg, i.t.) and R-α-methylhistamine (50 μg, 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 μg) 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.