cardiovascular-agents and Neuralgia

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Topics: Animals; Cardiovascular Agents; Cerebral Cortex; Dendrites; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Lysine; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Neuralgia; Neurons; Pain Measurement; Potassium Channels; Pyrimidines; Receptors, Serotonin; Serotonin; Serotonin Agents; Time Factors

Topics: Adolescent; Adult; alpha-Galactosidase; Cardiovascular Agents; Child; Contraindications; Delayed Diagnosis; Diagnosis, Differential; Disease Management; Enzyme Replacement Therapy; Fabry Disease; Female; Heart Diseases; Humans; Incidence; Infant, Newborn; Kidney Failure, Chronic; Leukocytes; Lysosomes; Male; Neuralgia; Renal Replacement Therapy

Peripheral nerve injury causes ectopic discharges of different firing patterns, which may play an important role in the development of neuropathic pain. The molecular mechanisms underlying the generation of ectopic discharges are still unclear. In the present study, by using in vivo teased fiber recording technique we examined the effect of ZD7288, a specific blocker of hyperpolarization-activated current (I(h)), on the ectopic discharges in the dorsal root ganglion (DRG) neurons injured by spinal nerve ligation. We found that ectopic discharges of all three firing patterns (tonic, bursting and irregular) were dose- and time-dependently inhibited by local application of ZD7288. Interestingly, the extent of suppression was negatively related to frequency of firing prior to application of ZD7288. We also observed that ZD7288 could alter the firing patterns of the ectopic discharges. At 100 microM, tonic firing pattern was gradually transformed into bursting type whereas at 1 mM, it could be transformed to integer multiples firing. These results indicate that I(h) might play a role in the generation of various forms of ectopic discharges in the injured DRG neurons and may thus be a possible target for neuropathic pain treatment.

Topics: Action Potentials; Animals; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Male; Neural Inhibition; Neuralgia; Neurons; Pyrimidines; Rats; Rats, Sprague-Dawley; Time Factors

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.. 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.

Topics: Animals; Axotomy; Cardiovascular Agents; Cations; Cyclic Nucleotide-Gated Cation Channels; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Ion Channels; Ligation; Male; Nerve Fibers, Myelinated; Neuralgia; Neurons, Afferent; Pain Threshold; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Pyrimidines; Rats; Rats, Sprague-Dawley; Spinal Nerve Roots; Spinal Nerves

Topics: Cardiovascular Agents; Causalgia; Hexamethonium; Muscle Relaxants, Central; Neuralgia; Phenoxybenzamine; Sympatholytics

Topics: Cardiovascular Agents; Dihydroergotamine; Ergot Alkaloids; Humans; Neuralgia; Trigeminal Neuralgia