Histamine H(3) receptors (H(3)Rs), 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, H(3)Rs 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 H(3)Rs 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 H(3)Rs 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 H(3)R agonists might be useful
analgesics, but these drugs have not been tested in clinically relevant
pain models. Paradoxically, H(3) 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 H(3) inverse agonist
thioperamide releases neuronal
histamine and mimics
histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H(3) 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.