H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats

The histamine H₄ receptor (H₄R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H₄R in pain transmission, the effects of JNJ7777120, a potent and selective H₄ antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED₅₀ = 17 mg/kg s.c., 95% CI = 8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED₅₀ = 22 mg/kg i.p., 95% CI = 10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H₁R antagonist diphenhydramine, H₂R antagonists ranitidine, or H₃R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED₅₀ of 29 mg/kg i.p. (95% CI = 19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED₅₀ = 60 mg/kg) and sciatic nerve constriction injury (ED₅₀ = 88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED₅₀ = 68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H₄ receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.