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Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia
S R Chaplan1, J W Pogrel, T L Yaksh
1Anesthesiology Research Laboratory, University of California, San Diego.
Abstract:
Peripheral nerve lesions can result in exaggerated pain responses to low intensity mechanical stimuli (tactile allodynia). In the present work, the pharmacology of voltage-dependent calcium channels (VDCCs) involved in the transmission of neuropathic pain was characterized by examining the effects of antagonists specific to the N-, L- and P-type VDCCs, as well as an antagonist at a non-L-, non-N-type site. Drugs were administered via chronic lumbar intrathecal, i.v. or regional nerve block catheters implanted in rats with tactile allodynia induced by tight ligation of the left fifth and sixth lumbar spinal nerves. Intrathecally delivered N-type VDCC (omega-conopeptides SNX239, SNX159 and SNX111) produced dose-dependent blockade of tactile allodynia. Intrathecal L-type (diltiazem, verapamil and nimodipine), non-N-, non-L-type (omega-conopeptide SNX230) and P-type (omega-agatoxin IVA) VDCC antagonists had no effect on pain behavior at the highest doses examined. No VDCC antagonist suppressed paw withdrawal when administered i.v. SNX239, although effective when administered intrathecally, was without effect when applied regionally to the injured portion of the nerve. These results emphasize the importance of N-type, but not L- or P- type, VDCCs in the spinal cord on systems mediating persistent tactile allodynia after nerve injury.
Insights
N-type voltage-dependent calcium channels (VDCCs) in the spinal cord are crucial for neuropathic pain transmission. Blocking these N-type VDCCs effectively reduced tactile allodynia in rats following nerve injury.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Peripheral nerve lesions can cause tactile allodynia, an exaggerated pain response to light touch.
- Voltage-dependent calcium channels (VDCCs) are implicated in the transmission of neuropathic pain signals.
Purpose of the Study:
- To characterize the role of different VDCC subtypes (N-, L-, P-type) in spinal cord pathways mediating tactile allodynia.
- To investigate the efficacy of specific VDCC antagonists in a rat model of neuropathic pain.
Main Methods:
- Rats with surgically induced tactile allodynia were treated with intrathecal, intravenous, or regional nerve block administration of VDCC antagonists.
- Antagonists targeted N-type (omega-conopeptides SNX239, SNX159, SNX111), L-type (diltiazem, verapamil, nimodipine), P-type (omega-agatoxin IVA), and non-N/L-type (omega-conopeptide SNX230) VDCCs.
Main Results:
- Intrathecal administration of N-type VDCC antagonists dose-dependently blocked tactile allodynia.
- L-type, P-type, and non-N/L-type VDCC antagonists showed no effect on pain behavior at the highest doses.
- Intravenous or regional nerve block administration of antagonists was ineffective.
Conclusions:
- N-type VDCCs in the spinal cord play a critical role in mediating persistent tactile allodynia after peripheral nerve injury.
- L-type and P-type VDCCs are not significantly involved in this specific pain pathway.
- Targeting spinal N-type VDCCs represents a potential therapeutic strategy for neuropathic pain.