HISTAMINE H4 RECEPTOR ACTIVATION INDUCES ANTINOCICEPTION IN A NEUROPATHIC PAIN MODEL

Current pharmacological treatment for neuropathic pain is unsatisfactory in many cases due to limited efficacy and side-effects. Further investigation of neuropathic pain pathophysiology is necessary for validating new pharmacological treatments to achieve efficient analgesia. Histamine has been widely implicated in the development of nociception and neuropathic pain. Histamine H1, H2 and H3 receptor ligands have been shown to reduce hyperalgesia following nerve injury, but the role of histamine H4 receptors (H4R) has not been fully elucidated. To investigate the role of histamine H4R in neuropathic pain, the H4R agonists VUF8430 (full agonist) and ST1006 (partial agonist) were used to assess their effects following peripheral nerve injury. Mice subjected to spared nerve injury (SNI), a model of neuropathic pain, showed a long lasting mechanical (von Frey’s test) and thermal (plantar test) hyperalgesia. I.c.v. administration of VUF8430 (20 µg/µl) and ST1006 (30 µg/µl) reversed pain hypersensitivity in the ipsilateral hind limb (n = 6; P<0.0001), while the highest doses, induced antinociception in the contralateral limb (n = 6; P<0.001). The time course of the anti-hyperalgesic and anti-allodynic effect is dose dependently and long lasting since both agonists reversed pain hypersensitivity at 30 min after administration and is still significant after 60 min. The increase of nociceptive threshold was completely prevented by the H4R antagonist JNJ10151984 (6 mg/kg p.o.) that was devoid of any effect when administered alone. Mice undergoing treatment with H4R receptor ligands did not show any side effects or signs of toxicity. To further investigate into the mechanisms of action of H4R agonists, we determined the capability of these compounds to counteract the oxidative damage induced by nerve injury. A significant increase of Poly(ADPribose) polymerase (PARP) activity and 8-hydroxy-20- deoxyguanosine (8OHdG) and decrease of mitochondrialsuperoxide dismutase (MnSOD) was observed in the ipsilateral spinal cord and sciatic nerve of SNI mice (n = 6; P<0.001). These effects were completely prevented by VUF8430 (P<0.0001). No effect was detected on the contralateral limb. This study presents evidence for a thermal and mechanical antinociception by H4R agonists in a model of neuropathic pain through an antioxidant mechanism. H4R activation may represent a new therapeutic perspective for neuropathic pain management.