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)

Neuropathic pain may be effectively relieved by electric stimulation of the spinal cord (SCS). However, the underlying mechanisms for the ensuing pain relief are poorly understood. In a rat model of neuropathy displaying hypersensitivity to innocuous tactile stimuli, (allodynia), we have earlier demonstrated that SCS may normalise withdrawal response thresholds. In the present study, using microdialysis, it is shown that SCS induces a decreased release of the dorsal horn excitatory amino acids (EAA), glutamate and aspartate, concomitant with an increase of the GABA release. Local perfusion with a GABA(B)-receptor antagonist in the dorsal horn transiently abolishes the SCS-induced suppression of the EAA release. Thus, the effect of SCS on neuropathic pain and allodynia may be due to an activation of local GABAergic mechanisms inhibiting the EAA release which is chronically elevated in such conditions.
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PMID:Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. 941 60

Neuropathic pain, whether of peripheral or central origin, is characterized by a neuronal hyperexcitability in damaged areas of the nervous system. In peripheral neuropathic pain, damaged nerve endings exhibit abnormal spontaneous and increased evoked activity, partly due to an increased and novel expression of sodium channels. In central pain, although not explored in detail, the spontaneous pain and evoked allodynia are also best explained by a neuronal hyperexcitability. The peripheral hyperexcitability is due to a series of molecular changes at the level of the peripheral nociceptor, in dorsal root ganglia, in the dorsal horn of the spinal cord, and in the brain. These changes include abnormal expression of sodium channels, increased activity at glutamate receptor sites, changes in gamma-aminobutyric acid (GABA-ergic) inhibition, and an alteration of calcium influx into cells. The neuronal hyperexcitability and corresponding molecular changes in neuropathic pain have many features in common with the cellular changes in certain forms of epilepsy. This has led to the use of anticonvulsant drugs for the treatment of neuropathic pain. Carbamazepine and phenytoin were the first anticonvulsants to be used in controlled clinical trials. Studies have shown these agents to relieve painful diabetic neuropathy and paroxysmal attacks in trigeminal neuralgia. Subsequent studies have shown the anticonvulsant gabapentin to be effective in painful diabetic neuropathy, mixed neuropathies, and postherpetic neuralgia. Lamotrigine, a new anticonvulsant, is effective in trigeminal neuralgia, painful peripheral neuropathy, and post-stroke pain. Other anticonvulsants, both new and old, are currently undergoing controlled clinical testing. The most common adverse effects of anticonvulsants are sedation and cerebellar symptoms (nystagmus, tremor and incoordination). Less common side-effects include haematological changes and cardiac arrhythmia with phenytoin and carbamazepine. The introduction of a mechanism-based classification of neuropathic pain, together with new anticonvulsants with a more specific pharmacological action, may lead to more rational treatment for the individual patient with neuropathic pain.
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PMID:Anticonvulsants in neuropathic pain: rationale and clinical evidence. 1188 43

Neuropathic pain models, such as the chronic constriction injury (CCI) model, are partial nerve injury models where there exist both intact and injured peripheral axons. Recent studies suggested that dorsal root ganglion (DRG) neurons with intact axons also show the alteration of excitability and gene expression and might have some role in the pathophysiological mechanisms of neuropathic pain. The incidence of pain-related behavior after the CCI is unstable and variable. In the present study, we used activating transcription factor 3 (ATF3) expression as a neuronal injury marker, and analyzed a relationship between the number of axotomized neurons and the incidence of pain-related behavior. We divided all rats into three groups according to the percentage of ATF3-immunoreactive (IR) neurons, group 1 (<12.5%), group 2 (12.5-25%), and group 3 (>25%). We found that rats in groups 2 and 3 showed thermal hyperalgesia, whereas only the rats in group 2 developed tactile allodynia from the third day to the fourteenth day after surgery. Rats in group 1 did not show thermal hyperalgesia or tactile allodynia. The DRG neurons in group 2 contained ATF3-IR neurons mainly in medium- and large-sized neurons. In order to investigate brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid(A)-receptor (GABA(A)-R) regulation in both intact and injured primary afferent neurons after the CCI, we used a double-labeling method with immunohistochemistry and in situ hybridization, as well as double immunofluorescent staining. The CCI induced an increased number of BDNF-labeled neurons in the ipsilateral DRG and the increase in BDNF expression was observed mainly in small- and medium-sized neurons that were mainly ATF3-negative. On the other hand, the number of GABA(A)-Rgamma2 subunit mRNA-positive neurons decreased in the ipsilateral DRG and GABA(A)-R- and ATF3-labeled neurons rarely overlapped. These changes in molecular phenotype in intact and injured primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by partial nerve injury.
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PMID:Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. 1250 1

Neuropathic pain is a common phenomenon resulting from injury to the central or peripheral nervous system. The means by which diabetes results in nerve injury is unclear but the effect is to cause injury at all levels of the nervous system from the level of the peripheral nerves to the brain. Nerve injury causes pain through a cascade of mechanisms resulting in altered processing of sensory input into the nervous system. This alteration occurs through chemical and anatomical changes in the nervous system that are similar to some of the processes seen in central sensitisation following acute pain. Following nerve injury, neuropathic pain occurs not only when these mechanisms are activated but also when sensitisation is maintained. Other processes occurring in neuropathic pain appear to be a loss of normal inhibitory controls as seen by a reduction in local GABA-ergic and descending monoaminergic influences. There are also important changes mediated via glial cells that can maintain neuropathic pain. Diabetes affects all areas of the nervous system and the contribution of higher levels of the nervous system is often overlooked. Neurophysiological and MRI evidence strongly suggest that these may contribute to the pain of diabetic neuropathy. Psychological dysfunction in diabetic patients is an important factor in increasing the suffering associated with all aspects of the disease, but treatment and control of pain can greatly improve the quality of life.
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PMID:Neuropathic pain and diabetes. 1257 53

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.
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PMID:Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain. 1449 51

Neuropathic pain is characterised by both positive (hyperalgesia and allodynia) and negative (sensory deficits) symptoms and remains intractable to many commonly used analgesics. Antiepileptics are increasingly utilised in the treatment of neuropathic pain. This class of drugs works via three major mechanisms of action in order to dampen neuronal hyperexcitability within the central nervous system: potentiation of GABA transmission, reduction of glutamate-mediated excitatory transmission, and block of voltage-activated ion channels. The latter mechanism of action in particular, is exemplified by the success of the newer generation of antiepileptics such as lamotrigine and gabapentin in the clinical treatment of neuropathic pain symptoms. In the current review article, we will examine in detail, the antinociceptive effects of a diverse range of antiepileptics as tested in animal models of nerve injury. Where appropriate, we will compare these findings with their analgesic efficacy in the clinical treatment of neuropathic pain.
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PMID:Antiepileptics and the treatment of neuropathic pain: evidence from animal models. 1617 54

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.
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PMID:BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. 1635

Neuropathic pain is a condition affecting a significant proportion of the world's population. Many therapeutic drugs have been used. They achieve less than satisfactory results and are associated to common side effects that affect the daily life of patients. Pregabalin is a new drug that has been shown to be effective for treating partial epilepsy and peripheral neuropathic pain in clinical trials. It is a structural, but not functional, analogue of GABA. It acts as a ligand of the alpha2-delta subunit, a protein associated to the voltage-dependent calcium channels. Modulation of these channels decreases calcium entry into nerve endings, resulting in a decreased release of several excitatory neurotransmitters. Pregabalin had a linear pharmacokinetics with little variability between the different subjects. It does not bind to plasma proteins, has no liver metabolism, and is excreted trough the kidneys. Few interactions with other drugs may be expected based on these characteristics. In clinical trials, pregabalin has been shown to be effective in postherpetic neuralgia and painful diabetic neuropathy at doses ranging from 150-600 mg/day. The analgesic effects of pregabalin occur in the first few days of treatment and are sustained over time. Side effects are few; most are transient and well-tolerated by patients, and the treatment discontinuation rate is minimal.
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PMID:[Pregabalin. A new treatment for neuropathic pain]. 1652 16

Under physiological conditions, nociceptive information is mainly processed in superficial laminae of the spinal dorsal horn, whereas non-nociceptive information is processed in deeper laminae. Neuropathic pain patients often suffer from touch-evoked pain (allodynia), suggesting that modality borders are disrupted in their nervous system. We studied whether excitation evoked in deep dorsal horn neurons either via stimulation of primary afferent Abeta-fibres, by direct electrical stimulation or via glutamate microinjection leads to activation of neurons in the superficial dorsal horn. We used Ca(2+)-imaging in transversal spinal cord slices of neuropathic and control animals to monitor spread of excitation from the deep to the superficial spinal dorsal horn. In neuropathic but not control animals, a spread of excitation occurred from the deep to the superficial dorsal horn. The spread of excitation was synaptically mediated as it was blocked by the AMPA receptor antagonist CNQX. In contrast, block of NMDA receptors was ineffective. In control animals, the violation of modality borders could be reproduced by bath application of GABA(A) and glycine receptor antagonists. Furthermore, we could show that neuropathic animals were more prone to synchronous network activity than control animals. Thus, following peripheral nerve injury, excitation generated in dorsal horn areas which process non-nociceptive information can invade superficial dorsal horn areas which normally receive nociceptive input. This may be a spinal mechanism of touch-evoked pain.
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PMID:Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. 1826 62

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.
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PMID:Pharmacological management of neuropathic pain following spinal cord injury. 1848 90


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