Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0423716 (Neuropathic pain)
 1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dorsal root ganglion (DRG) neurons have peripheral terminals in skin, muscle, and other peripheral tissues, and central terminals in the spinal cord dorsal horn. Hyperpolarization-activated current (I(h)) of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are present in the DRG. The genes encoding HCN channels have four subtypes named HCN1 to HCN4. HCN channels are permeable to both K(+) and Na(+). They underlie the depolarization that modulates the rhythmic generations of action potentials (APs), contribute to the resting membrane potential, and modify the waveform of propagated synaptic and generator potentials. Neuropathic pain is characterized by spontaneous pain, hyperalgesia and allodynia. After spinal nerve injury, the cell bodies of the primary sensory neurons in segmental DRG become hyperexcitable, characterized for some neurons by the presence of spontaneous firing (or ectopic discharge). In the following, we summarize our observations on the role of HCN channels in DRG neurons in neuropathic pain. 1 HCN subtypes and I(h) in DRG neurons Immunohistochemical staining revealed a subgroup of neurons in the DRG that were stained with rabbit polyclonal antibodies specific for HCN1, 2, 3 and 4. The most prominently expressed HCN subtype was HCN1. HCN1-positive cells in DRG were medium to large in size and doubly labeled with neurofilament-200 (NF-200), and were not labeled with isolectin B4 (IB4), a C fiber marker. In contrast, HCN2, 3 or 4 was expressed in all DRG neurons at a lower level. HCN4 was confined to small neurons. DRG neurons expressed I(h). When membrane was hyperpolarized, the channel was activated, mediating a slowly activated, inward current. I(h) was distributed mainly in large and medium-sized DRG neurons. 2 Changes in expression of HCN in DRG after spinal nerve ligation Western blotting was used to detect the changes in the expression of HCN subtypes in the DRG after spinal nerve ligation. HCN1 mRNA and protein were reduced in the DRG whose spinal nerve had been ligated. HCN1 expression was decreased to the lowest level at day 14 and restored at day 28 after spinal nerve ligation. HCN2 mRNA and medium molecular weight protein was also decreased in spinal-nerve ligated DRG. HCN3 and 4 in the same ganglion remained unchanged as evidenced by immunohistochemical staining, until day 28 when they became significantly decreased. HCN4 mRNA in DRG did not change, and protein expression slightly increased. Interestingly, abundant axonal accumulation of HCN channel protein at the injured sites in chronic constriction injury (CCI) rats. Electron immunomicroscopy showed strong positive immunolabeling on the axolemma of myelinated thick axons. 3 Role of I(h) in neuronal excitability and ectopic discharges after spinal nerve ligation ZD7288, a specific I(h) blocker, inhibited I(h) in a time- and concentration-dependent manner. With patch-clamp recording on acutely isolated DRG neurons, it was found that ZD7288 perfusion resulted in a decrease of both I(h) activity and the activation time constant. ZD7288 decreased the number of repetitive APs and caused an increase in AP rise time, accompanied by a small hyperpolarization of the membrane resting potential. The results demonstrated that I(h) was involved in AP firing, and possessed the physiological functions to facilitate neuronal excitability and ectopic firing. Extracellular electrophysiological recording from dorsal root fibers associated with the spinal nerve-ligated ganglion revealed three different firing patterns of ectopic discharges: tonic or regular, bursting and irregular. The average frequency of ectopic discharges and the proportions of active filaments also changed rapidly, both parameters reaching a peak within 24 h then declining gradually in the following days. It was also found that proportions of three different firing patterns changed dynamically over time. The tonic and bursting types were dominant patterns in the first 24 h, while the irregular became the only pattern at day 14. We found that all three firing patterns (tonic, bursting and irregular) were dose- and time-dependently inhibited by local application of ZD7288 to DRG. The rate of suppression was negatively related to the frequency of firing prior to the application of ZD7288. We also found that, while the tonic firing pattern was gradually transformed to bursting type by application of 100 mumol/L ZD7288, it could be transformed to integer multiples firing by 1000 mumol/L ZD7288. 4 Effects of administration of ZD7288 on mechanical allodynia after spinal nerve ligation or CCI After spinal nerve ligation, i.t. injection of 30 mug ZD7288 significantly increased the 50% paw withdrawal threshold, ipsilateral to the ligated nerve. ZD7288 had no effect if the dose was lower than 15 mug, but resulted in motor deficits if the dose was higher than 60 mug. ZD7288 produced much better effects in the early stage (5 or 14 days after spinal nerve ligation) than that in the late stage (28 days after spinal nerve ligation). In CCI rats, ZD7288 application to the injured sited also significantly suppressed the ectopic discharges from injured nerve fibers with no effect on impulse conduction. Moreover, mechanical allodynia was inhibited. In conclusion, these results demonstrated that I(h) participated in the development and maintenance of peripheral sensitivity associated with neuropathic pain and that it is a potential target for the design of novel analgesics in the future.
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PMID:Involvement of hyperpolarization-activated, cyclic nucleotide-gated cation channels in dorsal root ganglion in neuropathic pain. 1895 63

The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.
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PMID:HCN2 ion channels play a central role in inflammatory and neuropathic pain. 2190 16

Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family - better known for their role in the pacemaker potential of the heart - play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain.
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PMID:HCN2 ion channels: an emerging role as the pacemakers of pain. 2261 84

Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.
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PMID:HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain. 2762 81

Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord. Rats were subjected to CCI with or without pulsed electromagnetic field (PEMF) therapy. It was found that CCI induced neural cell degeneration while PEMF promoted nerve regeneration as documented by Nissl staining. CCI shortened the hind paw withdrawal latency (PWL) and hind paw withdrawal threshold (PWT) and PEMF prolonged the PWL and PWT. In addition, CCI lowers the expression of HCN1 and HCN2 mRNA and PEMF cannot restore the expression of HCN1 and HCN2 mRNA. Our results indicated that PEMF can promote nerve regeneration and could be used for the treatment of neuropathic pain.
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PMID:The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy. 2790 76