Hyperpolarization-activated, cation-nonselective, cyclic nucleotide-modulated channel blockade alleviates mechanical allodynia and suppresses ectopic discharge in spinal nerve ligated rats.
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 mumol/L) of ZD7288 for 5 minutes in vitro almost completely blocked ectopic discharges from large myelinated fibers (Abeta) while partially suppressing ectopic discharge from thinly myelinated fibers (Adelta). 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.


CONCLUSIONS
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.
Johnson and Johnson Pharmaceutical Research and Development, San Diego, California, USA. dool@amgen.com
Doo H
DH
Lee
Leon
L
Chang
Linda S
LS
Sorkin
Sandra R
SR
Chaplan
D000818:Animals; D019771:Axotomy; D002317:Cardiovascular Agents / Q000494:pharmacology; D002412:Cations / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008026:Ligation; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology; D013127:Spinal Nerves / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology
D002317:Cardiovascular Agents; D002412:Cations; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D011743:Pyrimidines; C082246:ICI D2788