strychnine and Peripheral-Nerve-Injuries

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA

Topics: Animals; Bicuculline; Disease Models, Animal; Glycine; Hyperalgesia; Imidazoles; Inhibitory Postsynaptic Potentials; Male; Mice, Inbred C57BL; Neurons; Neurotransmitter Agents; Peripheral Nerve Injuries; Phenanthrolines; Potassium Channels, Inwardly Rectifying; Receptors, GABA-A; Receptors, Glycine; Strychnine; Synaptic Transmission; Tissue Culture Techniques; Touch

When a peripheral nerve is severed, damaged sensory fibers emit a barrage of impulses that lasts for many seconds, or even several minutes ('injury discharge'). We have shown in rats that local anesthetic blockade of this discharge suppresses autotomy (a behavioral model of neuropathic pain). Correspondingly, mimicking prolonged injury discharge with electrical stimulation, especially of C-fibers, increased autotomy. These data support the hypothesis that injury discharge plays a role in the triggering of neuropathic pain. The mechanism of triggering autotomy was investigated using intrathecal injection of agents affecting glutamatergic transmission. A single intrathecal injection at the lumbar enlargement of the NMDA receptor blockers MK-801 and 5-APV, just prior to neurectomy, significantly suppressed autotomy. Blocking glycinergic inhibition just prior to neurectomy with a single strychnine injection strikingly enhanced autotomy. Strychnine enhancement of autotomy was prevented by prior injection of MK-801 or 5-APV. These results suggest that the expression of autotomy in rats, and by inference neuropathic pain in humans, is affected by injury discharge, possibly mediated by long-lasting, NMDA receptor-related, spinal disinhibition.

Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Dizocilpine Maleate; Electric Stimulation; Glutamates; Glutamic Acid; Glycine; Injections, Spinal; Male; Pain; Peripheral Nerve Injuries; Rats; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Strychnine

The effects of systemic administration of strychnine (1 mg/kg), picrotoxin (0.5 mg/kg) and bicuculline (2 mg/kg) on acute transsynaptic destruction of medullary dorsal horn neurons following transection of the inferior alveolar nerve were assessed in rats. Single intraperitoneal injections of the above drugs were given without, 1 min before or 1 min after the nerve transection. The effect of transection without drug administration was also examined. Eighteen hours after nerve transection without drug, approximately 7 dark neurons were found in a single toluidine blue stained 1 micron section of the rostral medullary dorsal horn ipsilateral to the nerve transection. Administration of the drugs 1 min before the nerve transection significantly increased the number of dark neurons in a single section to about 17 (strychnine), 46 (picrotoxin) and 20 (bicuculline). These dark neurons were found mainly in the dorsal half of medullary dorsal horn. Delivery of any of the drugs 1 min after the nerve transection did not increase the number of dark neurons. The data thus indicate that the transneuronal effect of transection of the nerve was enhanced by antagonism of glycinergic and GABAergic inhibition of dorsal horn neurons. In view of the short latency and duration of transsynaptic destructive activity, a massive injury discharge of primary afferent neurons and the subsequent release of excitatory neurotransmitters appear to be the direct cause of convulsant-enhanced rapid transsynaptic destruction which follows the peripheral nerve transection.

Topics: Animals; Bicuculline; Nerve Degeneration; Neurons; Peripheral Nerve Injuries; Peripheral Nerves; Picrotoxin; Rats; Rats, Inbred Strains; Strychnine