Peripheral block of the hyperpolarization-activated cation current (Ih) reduces mechanical allodynia in animal models of postoperative and neuropathic pain

Background and Objectives: Block of the hyperpolarization-activated inward current (I-h) reduces excitability of peripheral axons during stimulation and decreases ectopic discharges in axotomized sensory neurons. Changes in I-h expression in DRG neurons have been suggested to partially underlie sensitization after nerve injury and inflammation. We hypothesized that peripheral block of I-h on axons would produce an antiallodynic effect in postoperative as well as neuropathic conditions, and we tested perineural administration of ZD 7288, a specific blocker of I-h, on pain-associated behavior in animal models of neuropathic and postoperative pain. Methods: Under halothane anesthesia, partial sciatic nerve injury or hind-paw incision were performed on adult male rats as previously described. Mechanical allodynia was inferred by demonstration of a decrease in paw withdrawal threshold by application of calibrated von Frey filaments. After surgery, animals received either a saline or a ZD 7288 solution either by sciatic perineural injection or by intraplantar injection. Results: Perineural administration of ZD 7288 (100 AM) significantly reduced mechanical allodynia induced by partial sciatic nerve injury and hind-paw incision. Saline and 10 AM of ZD 7288 had no significant effect on mechanical allodynia. Contralateral administration of ZD 7288, 100 AM, did not affect ipsilateral paw withdrawal threshold after nerve injury. Intraplantar injection of ZD 7288 failed to reduce mechanical allodynia after nerve injury. Sedation and motor effects were not observed. Conclusions: The current study shows that peripheral block of I-h produces an antiallodynic effect, which suggests that I-h channels represent a novel target for nerve block treatment of postoperative and neuropathic pain.