Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.
Chronic pain is a major clinical problem and opiates are often the only treatment, but they cause significant problems ranging from sedation to deadly respiratory depression. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), causes a slow, sustained and irreversible activation of TRPV1 and increases the frequency of spontaneous excitatory postsynaptic currents, but causes significant depression of evoked EPSCs due to nerve terminal depolarization block. Intrathecal administration of RTX to rats in the short-term inhibits nociceptive synaptic transmission, and in the long-term causes a localized, selective ablation of TRPV1-expressing central sensory nerve terminals leading to long lasting analgesia in behavioral models. Since RTX actions are selective for central sensory nerve terminals, other efferent functions of dorsal root ganglion neurons can be preserved. Preventing nociceptive transmission at the level of the spinal cord can be a useful strategy to treat chronic, debilitating and intractable pain.
Jeffry
Joseph A
JA
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
Yu
Shuang-Quan
SQ
Sikand
Parul
P
Parihar
Arti
A
Evans
M Steven
MS
Premkumar
Louis S
LS
D000698:Analgesia; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism*
D004224:Diterpenes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C024353:resiniferatoxin; D002211:Capsaicin