Novel peripheral histamine H3 receptor antagonist ZPL-868087 attenuates mechanical hypersensitivity in neuropathic pain in mice

E. Battell1, A. Rosa2, P. Chazot3, R. L. Hiles1, A. Pini4, W. L. Liu5, I. Obara1. 1School of Medicine, Pharmacy and Health, Durham University, Stockton on Tees, UNITED KINGDOM, 2Department of Scienza e Tecnologia del Farmaco, University of Turin, Turin, ITALY, 3Department of Biosciences, Durham University, Durham, UNITED KINGDOM, 4Department of Clinical and Experimental Medicine, University of Florence, Florence, ITALY, 5Ziarco Pharma Limited, Canterbury, UNITED KINGDOM.

Introduction: Histamine H3 receptor (H3R) is expressed in nociceptive pathways and we identified H3R-containing A delta fibres as sources of high threshold mechanical nociception(1). There is also growing evidence supporting a role for H3R in the modulation of pain however many of the findings reporting the functional implication of H3R in chronic pain have been somewhat contradictory. Recent development of a selective and peripherally acting/centrally-sparing H3R ligand ZPL-868087(2) has provided an interesting tool for further investigation of the role of H3R in nociception and validation of peripheral H3R as a potential target for therapeutic intervention in chronic pain. We therefore evaluated the analgesic efficacy of ZPL-868087 in peripheral nerve injury-induced neuropathic pain and in a model of severe hyperglycaemia-induced hypersensitivity in mice.

Methods: Adult male C57BL/6J (B6) mice (n=6/group) were subjected to peripheral neuropathy induced by chronic constriction injury (CCI) of the sciatic nerve. The effect of ZPL-868087 (1, 3 and 10 mg/kg i.p.) on mechanical and heat hypersensitivity was determined 0.5, 1 and 24 h after each ZPL-868087 administrations (4 injections every 24 h for 4 days). In a separate experiment, adult male B6 mice (n=5-8/group) were subjected to severe hyperglycaemia-induced hypersensitivity developed after a single streptozotocin (STZ, 200 mg/kg i.p.) injection. Here, the effect of ZPL-868087 (10, 30 and 100 mg/kg p.o.) on mechanical and cold hypersensitivity was determined 1 and 24 h after each ZPL-868087 administrations (6 treatments every 24 h for 6 days). Mechanical, cold and heat hypersensitivity at the plantar surface of the hind paw was assessed using von Frey filaments and the acetone and Hargreaves tests. Analysis was performed using two-way ANOVA with Bonferroni’s test.

Results: In CCI mice, administration of ZPL-868087 resulted in alleviation of mechanical, but not heat hypersensitivity. Both 3 and 10 mg/kg significantly increased mechanical withdrawal threshold while 1 mg/kg was ineffective compare to vehicle controls (AUC - 10 mg: 7.14±0.97g, 3 mg: 6.79±0.91g, 1 mg: 2.38±0.44g, vehicle: 2.92±0.64g, P=0.0002). In STZ-treated mice, only 100 mg/kg inhibited mechanical hypersensitivity (AUC - 100 mg: 10.91±1.13g vs. STZ: 3.66±0.59g, P<0.0001). None of ZPL-868087 doses affected cold hypersensitivity or influenced nociceptive thresholds in control STZ animals.

Conclusions: Our findings provide further evidence and emphasize the importance of the H3R in the modulation of chronic pain and in alleviation of, in particular, peripheral neuropathies.

References: 1. Cannon KE et al. (2007). Pain 129:76-92. 2. Lunn G et al. (2012). Med Chem Commun 3:339-343.