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Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats.
Neuroscience. 2015 Jun 04; 295:90-102.N

Abstract

A hallmark of peripheral neuropathic pain (PNP) is chronic spontaneous pain and/or hypersensitivity to normally painful stimuli (hyperalgesia) or normally nonpainful stimuli (allodynia).This pain results partly from abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. We have previously shown, using a modified version of the lumbar 5 (L5)-spinal nerve ligation model of PNP (mSNA model involving L5-spinal nerve axotomy plus loose ligation of the lumbar 4 (L4)-spinal nerve with neuroinflammation-inducing chromic-gut), that L4 DRG neurons exhibit increased spontaneous activity, the key characteristic of neuronal hyperexcitability. The underlying ionic and molecular mechanisms of the hyperexcitability of L4 DRG neurons are incompletely understood, but could result from changes in expression and/or function of ion channels including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are active near the neuron's resting membrane potential, and which produce an excitatory inward current that depolarizes the membrane potential toward the threshold of action potential generation. Therefore, in the present study we used the mSNA model to investigate whether: (a) expression of HCN1-HCN3 channels is altered in L4 DRG neurons which, in the mSNA model, are essential for transmission of the evoked pain, and which contribute to chronic spontaneous pain, and (b) local (intraplantar) blockade of these HCN channels, with a specific blocker, ZD7288, attenuates chronic spontaneous pain and/or evoked pain in mSNA rats. We found 7days after mSNA: (1) a significant increase in HCN2-immunoreactivity in small (<30μm) DRG neurons (predominantly IB4-negative neurons), and in the proportion of small neurons expressing HCN2 (putative nociceptors); (2) no significant change in HCN1- or HCN3-immunoreactivity in all cell types; and (3) attenuation, with ZD7288 (100μM intraplantar), of chronic spontaneous pain behavior (spontaneous foot lifting) and mechanical, but not, heat hypersensitivity. The results suggest that peripheral HCN channels contribute to mechanisms of spinal nerve injury-induced PNP, and that HCN channels, possibly HCN2, represent a novel target for PNP treatment.

Authors+Show Affiliations

Department of Molecular and Clinical Pharmacology, Sherrington Buildings, University of Liverpool, L69 3GE, UK.Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.Department of Molecular and Clinical Pharmacology, Sherrington Buildings, University of Liverpool, L69 3GE, UK.Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia. Electronic address: ldjouhri@ksu.edu.sa.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25813712

Citation

Smith, T, et al. "Increased Expression of HCN2 Channel Protein in L4 Dorsal Root Ganglion Neurons Following Axotomy of L5- and Inflammation of L4-spinal Nerves in Rats." Neuroscience, vol. 295, 2015, pp. 90-102.
Smith T, Al Otaibi M, Sathish J, et al. Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats. Neuroscience. 2015;295:90-102.
Smith, T., Al Otaibi, M., Sathish, J., & Djouhri, L. (2015). Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats. Neuroscience, 295, 90-102. https://doi.org/10.1016/j.neuroscience.2015.03.041
Smith T, et al. Increased Expression of HCN2 Channel Protein in L4 Dorsal Root Ganglion Neurons Following Axotomy of L5- and Inflammation of L4-spinal Nerves in Rats. Neuroscience. 2015 Jun 4;295:90-102. PubMed PMID: 25813712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats. AU - Smith,T, AU - Al Otaibi,M, AU - Sathish,J, AU - Djouhri,L, Y1 - 2015/03/24/ PY - 2014/11/10/received PY - 2015/02/28/revised PY - 2015/03/19/accepted PY - 2015/3/28/entrez PY - 2015/3/31/pubmed PY - 2016/1/14/medline KW - HCN KW - dorsal root ganglion KW - neuropathic pain KW - pain hypersensitivity KW - primary sensory neurons KW - spontaneous pain SP - 90 EP - 102 JF - Neuroscience JO - Neuroscience VL - 295 N2 - A hallmark of peripheral neuropathic pain (PNP) is chronic spontaneous pain and/or hypersensitivity to normally painful stimuli (hyperalgesia) or normally nonpainful stimuli (allodynia).This pain results partly from abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. We have previously shown, using a modified version of the lumbar 5 (L5)-spinal nerve ligation model of PNP (mSNA model involving L5-spinal nerve axotomy plus loose ligation of the lumbar 4 (L4)-spinal nerve with neuroinflammation-inducing chromic-gut), that L4 DRG neurons exhibit increased spontaneous activity, the key characteristic of neuronal hyperexcitability. The underlying ionic and molecular mechanisms of the hyperexcitability of L4 DRG neurons are incompletely understood, but could result from changes in expression and/or function of ion channels including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are active near the neuron's resting membrane potential, and which produce an excitatory inward current that depolarizes the membrane potential toward the threshold of action potential generation. Therefore, in the present study we used the mSNA model to investigate whether: (a) expression of HCN1-HCN3 channels is altered in L4 DRG neurons which, in the mSNA model, are essential for transmission of the evoked pain, and which contribute to chronic spontaneous pain, and (b) local (intraplantar) blockade of these HCN channels, with a specific blocker, ZD7288, attenuates chronic spontaneous pain and/or evoked pain in mSNA rats. We found 7days after mSNA: (1) a significant increase in HCN2-immunoreactivity in small (<30μm) DRG neurons (predominantly IB4-negative neurons), and in the proportion of small neurons expressing HCN2 (putative nociceptors); (2) no significant change in HCN1- or HCN3-immunoreactivity in all cell types; and (3) attenuation, with ZD7288 (100μM intraplantar), of chronic spontaneous pain behavior (spontaneous foot lifting) and mechanical, but not, heat hypersensitivity. The results suggest that peripheral HCN channels contribute to mechanisms of spinal nerve injury-induced PNP, and that HCN channels, possibly HCN2, represent a novel target for PNP treatment. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/25813712/Increased_expression_of_HCN2_channel_protein_in_L4_dorsal_root_ganglion_neurons_following_axotomy_of_L5__and_inflammation_of_L4_spinal_nerves_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(15)00278-X DB - PRIME DP - Unbound Medicine ER -