Caspase signalling in neuropathic and inflammatory pain in the rat.

Abstract

Whereas small-fibre sensory neuropathies might ultimately lead to cell death and loss of sensation, they first progress through a phase, which might last for years, characterized by the presence of analgesia-resistant neuropathic dysesthesias and pain. Much previous research has addressed these two phases as separate phenomena mediated by presumably discrete biochemical mechanisms. We hypothesized that activity in signalling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurons becomes apparent. We have tested the hypothesis that activator and effector caspases, defining components of programmed cell death (apoptosis) signalling pathways, also contribute to pain-related behaviour in animals with small-fibre peripheral neuropathies and that the death receptor ligand, tumour necrosis factor-alpha, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. In two models of painful peripheral neuropathy, HIV/AIDS therapy (induced by the nucleoside reverse transcriptase inhibitor, dideoxycytidine), and cancer chemotherapy (induced by vincristine) peripheral neuropathy, and for pain-related behaviour induced by tumour necrosis factor-alpha and its second messenger, ceramide, inhibition of both activator (1, 2, 8 and 9) and effector (3) caspases attenuates neuropathic pain-related behaviour, although has no effect in streptozotocin-diabetic neuropathy and control rats. We conclude that during a latent phase, before apoptotic cell death is manifest, the caspase signalling pathway can contribute to pain in small-fibre peripheral neuropathies, and that inflammatory/immune mediators also activate these pathways. This suggests that these pathways are potential targets for novel pharmacological agents for the treatment of inflammatory as well as neuropathic pain.

• Authors: Elizabeth K Joseph, Jon D Levine
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 20 Issue 11 Pg. 2896-902 (Dec 2004) ISSN: 0953-816X [Print] France
• PMID: 15579143 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Caspase Inhibitors
• Ceramides
• Enzyme Inhibitors
• Neuroprotective Agents
• Tumor Necrosis Factor-alpha
• Vincristine
• Streptozocin
• Zalcitabine
• Caspases
• Dinoprostone
• Epinephrine

Topics

• Animals
• Caspase Inhibitors
• Caspases (physiology)
• Ceramides (pharmacology)
• Dinoprostone
• Dose-Response Relationship, Drug
• Drug Interactions
• Enzyme Inhibitors (pharmacology)
• Epinephrine
• Hyperalgesia (chemically induced, drug therapy)
• Male
• Neuralgia (drug therapy, etiology)
• Neurogenic Inflammation (chemically induced, complications, drug therapy, enzymology)
• Neuroprotective Agents (administration & dosage)
• Pain Measurement (drug effects)
• Pain Threshold (drug effects, physiology)
• Peripheral Nervous System Diseases (chemically induced, complications, drug therapy, enzymology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Streptozocin
• Time Factors
• Tumor Necrosis Factor-alpha (pharmacology)
• Vincristine
• Zalcitabine