title: Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats.
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: Department of Molecular and Clinical Pharmacology, Sherrington Buildings, University of Liverpool, L69 3GE, UK.
authors: T
authors: T
authors: Smith
authors: Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.
authors: M
authors: M
authors: Al Otaibi
authors: Department of Molecular and Clinical Pharmacology, Sherrington Buildings, University of Liverpool, L69 3GE, UK.
authors: J
authors: J
authors: Sathish
authors: Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia. Electronic address: ldjouhri@ksu.edu.sa.
authors: L
authors: L
authors: Djouhri
mesh_terms: D000588:Amines / Q000627:therapeutic use; D000818:Animals; D019771:Axotomy; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005260:Female; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D009437:Neuralgia / Q000150:complications / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011843:Radiculopathy / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013127:Spinal Nerves / Q000293:injuries; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D037102:Lectins; D011743:Pyrimidines; C082246:ICI D2788; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
keywords: HCN; dorsal root ganglion; neuropathic pain; pain hypersensitivity; primary sensory neurons; spontaneous pain