| Since activation of histamine H3 receptors attenuates peptide release from sensory fibers, it has been hypothesized that H3 receptors are located on peptidergic C fibers. Because the most well-known peptidergic C fibers are polymodal C nociceptors, this hypothesis implies that H 3 agonists should inhibit nociceptive transmission. Therefore, the present thesis work performed a detailed investigation into the antinociceptive profile of H3 agonists and immunohistochemical profile of H3 receptors in the skin, spinal cord, and dorsal root ganglia. The present studies revealed that the H3 agonist immepip produces modality- (mechanical vs. thermal) specific and intensity- (low vs. high mechanical) specific inhibition of nociception in rats. In addition, immepip significantly attenuated inflammation and paw flinching (but not licking) produced during the rat formalin test, a model for persistent nociception. Further studies revealed that immepip activated spinal H3 receptors to attenuate low-intensity mechanical and formalin-induced flinching. Immunohistochemical analyses revealed anti-H 3 receptor labeling on the spinal and peripheral branches of deep dermal, perivascular fibers of rats and wild type (but not H3 receptor knockout) mice. Because H3 receptors are located on the spinal and peripheral terminals of a discrete subset of small-caliber fibers, and activation of spinal H3 receptors is sufficient to attenuate low-intensity mechanical nociception, these findings strongly argue that H3 receptor-containing, deep dermal, peptidergic, perivascular AS fibers are necessary to evoke low-intensity mechanical nociceptive transmission. Furthermore, these findings also imply that activation of H3 receptor-containing, deep dermal, peptidergic, perivascular Adelta fibers is critical for the production of formalin-induced flinching responses and inflammation, but not for formalin-induced licking responses. These data challenge the current hypothesis that C fibers mediate both nociceptive flinching and licking responses following formalin injection and suggest that the contributions of C fibers is not necessary for the former responses. In addition, activation of spinal and peripheral H3 receptors located on these fibers inhibits flinching responses and paw swelling, respectively, produced by formalin. The antinociceptive profile described herein for immepip suggests that H3 agonists may be novel treatments for mechanical, deep dermal, and/or vascular pain syndromes. |
