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Title: The role of VPAC2 receptors and PKA in neuropathic pain
Author: Moss, A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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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) mice were attenuated. No morphological differences were seen between peripheral nerves of WT and VPAC2R (-/-) mice. Furthermore, intrathecal administration of a VPAC2R antagonist 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 CCL. In situ hybridisation for isoforms of PKA regulatory (R) and catalytic (C) subunits showed a spinal increase in C-subunit, but not R-subunit mRNAs ipsilaterally at the peak of CCI sensitisation. Immunoblots confirmed an ipsilateral increase in C-subunits and showed a bilateral decrease in the RIβ 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 inhibited 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 PGP 9.5 (a key enzyme is 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available