The selective TRPV4 channel antagonist HC-067047 attenuates mechanical allodynia in diabetic mice

• Published in: European journal of pharmacology Vol. 856; p. 172408
• Main Authors: Dias, Fabiana C., Alves, Vinícius S., Matias, Daiane O., Figueiredo, Claudia P., Miranda, Ana Luisa P., Passos, Giselle F., Costa, Robson
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.08.2019
• Subjects: Animals; Body Temperature - drug effects; Body Weight - drug effects; Diabetes; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Gene Expression Regulation - drug effects; HC-067047; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Locomotion - drug effects; Male; Mice; Morpholines - pharmacology; Morpholines - therapeutic use; Neuropathic pain; Psychomotor Performance - drug effects; Pyrroles - pharmacology; Pyrroles - therapeutic use; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; TRPV4; Diabetes; HC-067047; TRPV4; Neuropathic pain
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.172408

Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1 mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10 mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.