Pharmacological activation of
histamine H3 receptors is known to reduce the release of inflammatory
peptides, thereby reducing
pain and
inflammation, but the site(s) and mechanism(s) of these effects are currently unknown. The present study addressed these questions by examining the effects of the
H3 agonist immepip and the H3 antagonist
thioperamide on nociceptive behaviors and swelling produced during the rat
formalin test. Systemic administration of
immepip (5 and 30 mg/kg, s.c.) significantly attenuated
formalin-induced flinching but not licking responses during both phases. This attenuation was reversed by either systemic (15 mg/kg, i.p.) or intrathecal (20 or 50 microg) administration of
thioperamide. Furthermore,
immepip (30 mg/kg, s.c.) significantly inhibited
formalin-induced swelling, an action which was completely reversed by systemic (15 mg/kg, i.p.), but not intrathecal (50 microg)
thioperamide. Also consistent with this pattern, intrathecal
immepip (50 microg) reduced flinching responses, but had no effect on
formalin-induced paw swelling. The present findings suggest that activation of
H3 receptors located on peripheral and spinal terminals of deep dermal fibers attenuates
formalin-induced swelling and flinching, respectively. Pharmacological stimulation of
H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory
pain.