Noradrenergic fiber sprouting and altered transduction in neuropathic prefrontal cortex
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Functional changes in hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels have been shown to contribute to medial prefrontal (mPFC) hyperexcitability after peripheral nerve injury. A reduction in the open probability of these neuronal channels might be relevant since this can enhance membrane input resistance and synaptic summation. However, the molecular mechanisms underlying neuropathy-associated alterations in HCN channel activity remain elusive. Using the spared nerve injury model of neuropathic pain in Long–Evans rats, we first discovered a significant increase in noradrenergic innervation within the mPFC of nerve-injured compared to control animals. Patch-clamp recordings in layer II/III pyramidal neurons of the mPFC revealed that adrenoceptors, primarily the α2 subtype, can modulate the voltage-dependent activation of HCN channels and the abnormal prefrontal excitability following peripheral neuropathy. Additionally, microinfusions of the α2 adrenoceptor agonist clonidine in the mPFC of neuropathic rats provided analgesic effects, indicating the behavioral significance for this noradrenergic pathway in manifestations of the chronic pain state. Taken together, our results provide insights into the role of cortical catecholaminergic neuromodulation in neuropathic pain and suggest that altered noradrenergic transduction may play a major role in the HCN channel dysfunction and pyramidal hyperactivity observed in several chronic pain conditions.
KeywordsClonidine HCN channels Neuromodulation Monoamines Neuropathic pain
This work was supported by grants to PS from the Canadian Institutes of Health Research [MOP-130239] and the Natural Sciences and Engineering Council of Canada [DG-203061], and by grants to ARS from the Canadian Institutes of Health Research [MOP-79411]. SCM holds a Fonds de recherche du Québec-Santé (FRQS) doctoral studentship.
Conceived and designed the experiments: SCM and PS. Performed the experiments: SCM, MZ and GL. Analyzed the data: SCM and PS. Wrote the paper: SCM, ARS and PS.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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