Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H3 receptors

Histamine H 3 receptors have been suggested to inhibit the activity of a variety of central and peripheral neurons. Recent studies revealed that activation of spinal histamine H 3 receptors attenuates tail pinch, but not tail flick, nociception. To determine whether H 3 receptor-mediated antinociception is truly modality-specific, the effects of the selective H 3 agonist immepip were evaluated on nociceptive responses in rats induced by a range of thermal and mechanical intensities applied to the hind paw and the tail. In addition, the modulation of chemical nociceptive (ie, formalin) responses by immepip was evaluated. Immepip (5 to 30 mg/kg, subcutaneous) attenuated responses to low-intensity mechanical pinch, but not to high-intensity mechanical pressure applied to either the hind paw or the tail. The same doses of immepip had no effect on thermal nociceptive responses, regardless of the stimulus intensity. These results suggest that immepip-induced antinociception is modality- and intensity-specific. It is likely that immepip inhibits low-intensity mechanical nociception by activation of H 3 receptors located on the spinal terminals of Adelta and possibly C high-threshold mechanoreceptors. In addition, immepip (5 mg/kg, subcutaneous) significantly attenuated formalin-induced flinching, but not formalin-induced licking, during both phase 1 and phase 2, suggesting that H 3 agonists might be effective in treating some forms of clinically relevant pain. Certain classes of pain-transmitting fibers possess histamine H 3 receptors, but the localization and functional significance of these inhibitory receptors was not known. The present study shows that drugs that stimulate H 3 receptors can reduce behavioral responses produced by some, but not all, painful stimuli. Thus, H 3 agonists could be a new type of therapy for certain kinds of pain disorders.