H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Histamine H₃ receptors (H₃Rs), distributed within the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H₃Rs are found on certain Aβ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic Aδ fibers terminating on deep dermal blood vessels. Activation of H₃Rs on the latter in the skin, heart, lung, and dura mater reduces calcitonin gene-related peptide and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H₃Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to low-intensity mechanical stimuli and inflammatory stimuli such as formalin. These findings suggest that H₃R agonists might be useful analgesics, but these drugs have not been tested in clinically relevant pain models. Paradoxically, H₃ antagonists/inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaqueductal gray (an important pain regulatory center), the H₃ inverse agonist thioperamide releases neuronal histamine and mimics histamine9s biphasic modulatory effects in thermal nociceptive tests. Newer H₃ inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood.