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Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

Jeffry JA, Yu SQ, Sikand P, Parihar A, Evans MS, Premkumar LS - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.

ABSTRACT
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.

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Intrathecal administration of RTX reduced pain behavior induced by capsaicin and inflammation.A. Effect of increasing concentrations of RTX on PWL to radiant heat. B, C. nThe duration and the number of nocifensive behaviors after intraplantar capsaicin significantly decreased after RTX treatment D. PWL to a thermal stimulus after injection of carrageenan is significantly reduced as compared to saline injected animals.
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pone-0007021-g004: Intrathecal administration of RTX reduced pain behavior induced by capsaicin and inflammation.A. Effect of increasing concentrations of RTX on PWL to radiant heat. B, C. nThe duration and the number of nocifensive behaviors after intraplantar capsaicin significantly decreased after RTX treatment D. PWL to a thermal stimulus after injection of carrageenan is significantly reduced as compared to saline injected animals.

Mentions: Having demonstrated the unique properties of RTX at the first sensory synapse in the spinal cord and CSTN, we hypothesized that RTX-induced sustained activation of TRPV1 at the presynaptic terminal would cause analgesia by depression of synaptic transmission in the short-term and by nerve terminal ablation in the long-term. Therefore, we tested the effect of intrathecal administration of RTX in adult rats. RTX (0.045–1.9 µg/kg) was administered intrathecally in behavioral models of pain. Paw withdrawal latency (PWL) to radiant heat was not significantly affected following administration of RTX (control, 7.2±0.6 s, n = 8; RTX (1.9 µg/kg), 9.2±0.5 s, n = 8) (Fig. 4A). However, when tested for nocifensive behavior by intraplantar injection of capsaicin, a dramatic decrease in pain sensitivity was observed as indicated by reduction in the duration and number of guardings (Fig. 4B, C). The number of guardings decreased significantly from 12.5±2.8 (n = 6) to 4.8±1. 5 (n = 11, p<0.05) and the duration of guardings decreased significantly from 151.7±30.1 s (n = 6) to 49±19.9 s (n = 11, p<0.05) after RTX treatment. We then tested whether RTX treatment could selectively alleviate inflammatory thermal hypersensitivity. Inflammation was induced by carrageenan (2%, 100 µl) in the left paw and the right paw was used as a control. Following inflammation, the PWL of control animals decreased significantly from 7.6±0.5 s (n = 12) to 4.5±0.5 s, n = 6, p<0.05) (Fig. 4D). Intrathecal administration of RTX prevented the reduction in PWL caused by inflammation (control, 9.5±0.9 s (n = 10) and RTX, 8.5±0.4 s (n = 12). These studies indicate that intrathecal administration of RTX did not alter the acute thermal sensitivity but profoundly reduced inflammation-induced thermal hypersensitivity.


Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

Jeffry JA, Yu SQ, Sikand P, Parihar A, Evans MS, Premkumar LS - PLoS ONE (2009)

Intrathecal administration of RTX reduced pain behavior induced by capsaicin and inflammation.A. Effect of increasing concentrations of RTX on PWL to radiant heat. B, C. nThe duration and the number of nocifensive behaviors after intraplantar capsaicin significantly decreased after RTX treatment D. PWL to a thermal stimulus after injection of carrageenan is significantly reduced as compared to saline injected animals.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2737142&req=5

pone-0007021-g004: Intrathecal administration of RTX reduced pain behavior induced by capsaicin and inflammation.A. Effect of increasing concentrations of RTX on PWL to radiant heat. B, C. nThe duration and the number of nocifensive behaviors after intraplantar capsaicin significantly decreased after RTX treatment D. PWL to a thermal stimulus after injection of carrageenan is significantly reduced as compared to saline injected animals.
Mentions: Having demonstrated the unique properties of RTX at the first sensory synapse in the spinal cord and CSTN, we hypothesized that RTX-induced sustained activation of TRPV1 at the presynaptic terminal would cause analgesia by depression of synaptic transmission in the short-term and by nerve terminal ablation in the long-term. Therefore, we tested the effect of intrathecal administration of RTX in adult rats. RTX (0.045–1.9 µg/kg) was administered intrathecally in behavioral models of pain. Paw withdrawal latency (PWL) to radiant heat was not significantly affected following administration of RTX (control, 7.2±0.6 s, n = 8; RTX (1.9 µg/kg), 9.2±0.5 s, n = 8) (Fig. 4A). However, when tested for nocifensive behavior by intraplantar injection of capsaicin, a dramatic decrease in pain sensitivity was observed as indicated by reduction in the duration and number of guardings (Fig. 4B, C). The number of guardings decreased significantly from 12.5±2.8 (n = 6) to 4.8±1. 5 (n = 11, p<0.05) and the duration of guardings decreased significantly from 151.7±30.1 s (n = 6) to 49±19.9 s (n = 11, p<0.05) after RTX treatment. We then tested whether RTX treatment could selectively alleviate inflammatory thermal hypersensitivity. Inflammation was induced by carrageenan (2%, 100 µl) in the left paw and the right paw was used as a control. Following inflammation, the PWL of control animals decreased significantly from 7.6±0.5 s (n = 12) to 4.5±0.5 s, n = 6, p<0.05) (Fig. 4D). Intrathecal administration of RTX prevented the reduction in PWL caused by inflammation (control, 9.5±0.9 s (n = 10) and RTX, 8.5±0.4 s (n = 12). These studies indicate that intrathecal administration of RTX did not alter the acute thermal sensitivity but profoundly reduced inflammation-induced thermal hypersensitivity.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus