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The role of VPAC₂ receptors and PKA in neuropathic pain

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MossA_2002reduxOCR.pdf (37.70Mb)
Date
2002
Author
Moss, Andrew
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Abstract
 
 
In animal models of neuropathic pain, changes in afferent and spinal cord neurones after pe1ipheral nerve injury lead to hyperexcitability within the spinal dorsal horn, termed "central sensitisation". This causes a persistent pain state with enhanced responses to noxious stimuli (hyperalgesia) and pain-like responses to previously innocuous stimuli (allodynia).
 
The role of the VPAC₂ receptor in CCI was investigated. In VPAC₂R(⁻/⁻) mice, the enhanced reflex responses to noxious heat and innocuous mechanical stimulation seen in wild type (WT) mke were attenuated. No morihological differences were seen between peripheral nerves of WT and VPAC2R c--) mice. Furthermore, intrathecal administration of a VPAC₂R inhibitor attenuated the enhanced reflex withdrawal responses to noxious heat and innocuous mechanical stimuli in WT mice following CCI, with no effect in VPAC₂R (⁻/⁻) mice.
 
In normal rats, intrathecal administration of PKA inhibitors attenuated the enhanced reflex withdrawal responses due to CCI. In situ hybridisation for isofo1ms of PKA regulatory (R) and catalytic (C) subunits showed a spinal increase in C-subunit , but not R-subunit mRNA ipsilaterally at the peak of CCI sensitisation. Immunoblots confiimed an ipsilateral increase in C-subunits and showed a bilateral decrease in the RI~ subunit.
 
The role of the proteasome in neuropathic sensitisation was studied. Electrophysiological recordings made from dorsal horn neurones in anaesthetised rats showed that proteasome inhibitors applied by ionophoresis inhibi ted activity evoked by innocuous brush and cold in CCI rats, while nociceptive responses were inhibited in CCI and normal animals. Intrathecal administration of proteasome inhibitors attenuated the enhanced paw withdrawal behaviours ipsilateral to CCI. The mRNA and protein levels for UCH-Ll, (a key enzyme in proteasomal function) were increased ipsilaterally. PKA enzymatic activity was increased in spinal cord ipsilateral to nerve injury and this increment was prevented by topical application of proteasome inhibitors.
 
This investigation demonstrates the involvement of the VPAC₂ receptor, the corresponding cAMP/PKA signal transduction cascade and the proteasome (a regulator of PKA activity) in the spinal sensitisation caused by CCI.
 
URI
http://hdl.handle.net/1842/29898
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