title: Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex.
abstract: Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of Ih in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. Using the spared nerve injury (SNI) model of neuropathic pain in Long-Evans rats and patch-clamp recordings in layer II/III pyramidal neurons of the contralateral mPFC, we observed a hyperpolarizing shift in the voltage-dependent activation of Ih in SNI neurons, whereas maximal Ih remained unchanged. Accordingly, SNI mPFC pyramidal neurons exhibited increased input resistance and excitability, as well as facilitated glutamatergic mGluR5-mediated persistent firing, compared with sham neurons. Moreover, intracellular application of bromo-cAMP abolished the hyperpolarizing shift in the voltage-dependent activation of Ih observed in SNI neurons, whereas protein kinase A (PKA) inhibition further promoted this shift in both SNI and sham neurons. Behaviorally, acute HCN channel blockade by local injection of ZD7288 in the mPFC of SNI rats induced a decrease in cold allodynia. These findings suggest that changes in the cAMP/PKA axis in mPFC neurons underlie alterations to HCN channel function, which can influence descending inhibition of pain pathways in neuropathic conditions. Significance statement: Recent studies investigating the role of the medial prefrontal cortex (mPFC) in neuropathic pain have led to an increased awareness of how affective and cognitive factors can influence pain perception. It is therefore imperative that we advance our understanding of the involvement of supraspinal pain pathways. Our electrophysiological and behavioral results support an important role for hyperpolarization-activated cyclic nucleotide-gated channels and the cAMP/protein kinase A signaling axis in promoting hyperexcitability and persistent firing in pyramidal neurons of the mPFC in neuropathic animals. These findings offer novel insights, with potential therapeutic implications, into pathophysiological mechanisms underlying the abnormal contribution of layer II/III prefrontal pyramidal neurons to chronic pain states.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Cordeiro Matos
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Zizhen
authors.identifier: http://orcid.org/0000-0001-8069-3756
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 2B4, Canada philippe.seguela@mcgill.ca.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0001-7537-4427
authors.initials: P
authors.lastname: Séguéla
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D026941:Sodium Channel Blockers / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D011743:Pyrimidines; D026941:Sodium Channel Blockers; C082246:ICI D2788; D013779:Tetrodotoxin; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol
keywords: allodynia; anterior cingulate cortex; hyperexcitability; neuropathic pain; persistent firing