Noradrenergic fiber sprouting and altered transduction in neuropathic prefrontal cortex
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.
- Basbaum A, Jessell T (2013) Pain. In: Kandel E, Schwartz T, Jessel T, Siegelbaum S, Hudspeth A (eds) Principles of neural science, vol 24, 5th edn. The McGraw-Hill Companies, New York, pp 530–555Google Scholar
- He XT, Yu J, Li BM, Zhang XH (2014) The expression of alpha2A-adrenoceptors in the calcium-binding protein immunoreactive interneurons in rat prefrontal cortex. Acta Physiol Sin 66:537–544Google Scholar
- Koga K, Descalzi G, Chen T, Ko HG, Lu J, Li S, Son J, Kim T, Kwak C, Huganir RL, Zhao MG, Kaang BK, Collingridge GL, Zhuo M (2015) Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron 85:377–389CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (2014) The rat brain in stereotaxic coordinates, 7th edn. Elsevier Press, New YorkGoogle Scholar
- Thibault K, Lin WK, Rancillac A, Fan M, Snollaerts T, Sordoillet V, Hamon M, Smith GM, Lenkei Z, Pezet S (2014) BDNF-dependent plasticity induced by peripheral inflammation in the primary sensory and the cingulate cortex triggers cold allodynia and reveals a major role for endogenous BDNF as a tuner of the affective aspect of pain. J Neurosci 34:14739–14751CrossRefPubMedGoogle Scholar
- Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410CrossRefPubMedGoogle Scholar