Hyperpolarization-Activated, Cation-Nonselective, Cyclic Nucleotide-Modulated Channel Blockade Alleviates Mechanical Allodynia and Suppresses Ectopic Discharge in Spinal Nerve Ligated Rats

Abstract

Abnormal spontaneous firing is well described in axotomized sensory neurons and likely contributes to nerve injury-induced pain. The hyperpolarization-activated current I h initiates spontaneous, rhythmic depolarization in the sinoatrial node and central neurons. This study was undertaken to investigate the possible contribution of I h to primary afferent ectopic discharge and pain behavior in nerve-injured rats. Nerve injury was produced by tight ligation of lumbar spinal nerves (L5/6). Two weeks later, rats showed marked mechanical allodynia. Withdrawal thresholds were measured before and after administration of saline or the specific I h antagonist ZD7288 (1, 3, or 10 mg/kg, intraperitoneally). ZD7288 dose-dependently reversed mechanical allodynia. In a second experiment, we performed both in vivo and in vitro extracellular single unit recordings from teased dorsal root fascicles. Intravenous infusion (2.5 or 5 mg/kg) of ZD7288 during a period of 10 minutes significantly blocked ectopic discharges in vivo. Perfusion (25 to 100 μmol/L) of ZD7288 for 5 minutes in vitro almost completely blocked ectopic discharges from large myelinated fibers (Aβ) while partially suppressing ectopic discharge from thinly myelinated fibers (Aδ). We conclude from these data that in axotomized sensory neurons, a ZD7288-sensitive current contributes to spontaneous discharges in myelinated fibers. Thus, I h might substantially contribute to the pathophysiology of nerve injury-related neuropathic pain. Perspective The current study investigated the mechanism of abnormal spontaneous discharges (ectopic discharges) from axotomized sensory afferents. Ectopic discharges are a main driving source of nerve injury-induced neuropathic pain. Understanding the mechanism of ectopic discharges and identifying how to control them will be useful toward developing new therapies.