Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Limb amputation is followed by stump and phantom pain in a large proportion of amputees and postamputation pain may be associated with signs of hyperexcitability such as hyperalgesia to mechanical stimulation. The present study examined the possible relationship between mechanical pain threshold of the limb and early (after 1 week) and late (after 6 months) phantom pain. Thirty-five patients scheduled for amputation of the lower limb were examined before, 1 week and 6 months after amputation. On all three examination days pressure-pain thresholds were measured and compared with the simultaneous recording of ongoing pain intensity assessed on a visual analogue scale (VAS). There was a weak but significant inverse relationship between preamputation thresholds and early stump and phantom pain. There was no relationship between preamputation thresholds and late stump and phantom pain. One week after amputation there was a significant and inverse relationship between mechanical thresholds and phantom pain but no relationship was found after 6 months. The findings suggest that although tenderness of the limb before and after amputation is related to early stump and phantom pain, the relationship is weak. Neuronal sensitization peripherally or centrally may play a role in the development of phantom pain.
Eur J Pain 2000
PMID:Relationship between mechanical sensitivity and postamputation pain: a prospective study. 1112 4

In previous studies we provided evidence that the gamma isoform of protein kinase C (PKCgamma) is an important contributor to the increased pain sensitivity that occurs after injury. Here we combined electrophysiological and behavioral approaches in wild-type and PKCgamma-null mice to compare the hyperexcitability of wide dynamic range neurons in lamina V of the spinal cord dorsal horn with the behavioral hyperexcitability produced by the same injury [application of a C-fiber irritant, mustard oil (MO), to the hindpaw]. Wild-type and null mice did not differ in their response to mechanical or thermal stimuli before tissue injury, and the magnitude of the response to the MO stimuli was comparable. In wild-type mice, MO produced a dramatic and progressive enhancement of the response of lamina V neurons to innocuous mechanical and thermal stimuli. The time course of the neuronal hyperexcitability paralleled the time course of the MO-induced behavioral allodynia (nocifensive behavior in response to a previously innocuous mechanical stimulus). Neuronal hyperexcitability was also manifest in the PKCgamma-null mice, but it lasted <30 min. By contrast, the behavioral allodynia produced by MO in the PKCgamma-null mice, although reduced to approximately half that of the wild-type mice, persisted long after the lamina V hyperexcitability had subsided. Because the MO-induced behavioral allodynia was completely blocked by an NMDA receptor antagonist, we conclude that PKCgamma mediates the transition from short- to long-term hyperexcitability of lamina V nociresponsive neurons but that the persistence of injury-induced pain must involve activity within multiple NMDA-dependent spinal cord circuits.
 ...
PMID:PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. 1143 8

Within the last 2 decades there has been an explosion in new information on mechanisms underlying pain. Unfortunately this information has not resulted in a similar improvement of our handling of patients with chronic pain including chronic musculoskeletal pain. Neuronal hyperexcitability, which apparently is a key phenomenon in many (if not all) types of chronic pain results in changes in the nervous system from the level of the peripheral nociceptor to the highest cortical centers in the brain. The neuronal plastic changes in chronic pain conditions makes the nociceptive system amenable for treatment with several traditional as well as nontraditional types of interventions. Two treatment areas that seem worth exploring within chronic pain including headache concerns preventive measures and endogenous pain modulation.
 ...
PMID:Recent advances in pain research: implications for chronic headache. 1159 9

Tremor that occurs as a result of a cerebellar lesion, cerebellar tremor, is characteristically an intention tremor. Thalamic activity may be related to cerebellar tremor because transmission of some cerebellar efferent signals occurs via the thalamus and cortex to the periphery. We have now studied thalamic neuronal activity in a cerebellar relay nucleus (ventral intermediate-Vim) and a pallidal relay nucleus (ventralis oral posterior-Vop) during thalamotomy in patients with intention tremor and other clinical signs of cerebellar disease (tremor patients). The activity of single neurons and the simultaneous electromyographic (EMG) activity of the contralateral upper extremity in tremor patients performing a pointing task were analyzed by spectral cross-correlation analysis. EMG spectra during intention tremor often showed peaks of activity in the tremor-frequency range (1.9-5.8 Hz). There were significant differences in thalamic neuronal activity between tremor patients and controls. Neurons in Vim and Vop had significantly lower firing rates in tremor patients than in patients undergoing thalamic surgery for pain (pain controls). Other studies have shown that inputs to Vim from the cerebellum are transmitted through excitatory connections. Therefore the present results suggest that tremor in these tremor patients is associated with deafferentation of the thalamus from cerebellar efferent pathways. The thalamic X EMG cross-correlation functions were studied for cells located in Vim and Vop. Neuronal and EMG activity were as likely to be significantly correlated for cells in Vim as for those in Vop. Cells in Vim were more likely to have a phase lag relative to EMG than were cells in Vop. In monkeys, cells in the cerebellar relay nucleus of the thalamus, corresponding to Vim, are reported to lead movement during active oscillations at the wrist. In view of these monkey studies, the present results suggest that cells in Vim are deafferented and have a phase lag relative to tremor that is not found in normal active oscillations. The difference in phase of thalamic spike X EMG activity between Vim and Vop may contribute to tremor because lesions of pallidum or Vop are reported to relieve cerebellar tremor.
 ...
PMID:Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease. 1192 26

Neurostimulation for refractory angina pectoris is often advocated for its clinical efficacy. However, the recruited pathways to induce electroanalgesia are partially unknown. Therefore, we sought to study the effect of neurostimulation on experimentally induced cardiac nociception, using capsaicin as nociception-induced substance. Four different groups of male Wistar rats were pericardially infused with either saline or capsaicin with or without neurostimulation. Group StimCap was infused with capsaicin, and group StimVeh was infused with saline. Both groups were treated with neurostimulation. Group ShamCap was only infused with capsaicin without stimulation, whereas group ShamVeh was only infused with saline. Neuronal activation differences were assessed with cytochemical staining, revealing the cellular expression of c-fos. Pain behavior was registered on video and was quantitatively analyzed. In the StimCap and ShamCap groups, all animals exerted typical pain behavior, whereas in the StimVeh group only moderate changes in behavior were observed. Group ShamVeh animals were unaffected by the procedure. The upper thoracic spinal cord showed high numbers of c-fos-positive cells, predominantly in laminae III and IV in both StimCap and StimVeh groups. Almost no c-fos expression was noticed in groups ShamCap and ShamVeh in these sections of the spinal cord. In groups StimCap and ShamCap a significantly higher number of c-fos-positive cells in comparison with groups StimVeh and ShamVeh were noticed in the periambigus region, the nucleus tractus solitarius, and the paraventricular hypothalamus. In the paraventricular thalamus, periaqueductal gray, and central amygdala, no significant differences were noticed among the first three groups, and the c-fos concentration in these three groups was significantly higher than in group ShamVeh. It is concluded that neurostimulation does not influence capsaicin-induced cardiac nociceptive pain pulses to the central nervous system. Furthermore, capsaicin-induced cardiac pain and neurostimulation may utilize two different pathways.
 ...
PMID:Cardiac nociception in rats: neuronal pathways and the influence of dermal neurostimulation on conveyance to the central nervous system. 1266 34

Neuronal hyperexcitability is a key finding in patients with neuropathic pain. Contributing to hyperexcitability may be decreased activity in the endogenous pain inhibitory systems. The present study aimed at recruiting descending inhibition, by the use of painful heterotopic stimulation (HTS), in 16 patients with peripheral chronic neuropathic pain and associated brush-evoked allodynia. Two experiments were performed: one examined the effect of HTS on ongoing pain and intensity of brush-evoked allodynia and the other tested the effect of HTS on ongoing pain and area of brush-evoked allodynia. Both experiments consisted of two sessions, one with painful cold HTS (1 degrees C water bath) another with non-painful neutral HTS (32 degrees C water bath). The area of brush-evoked allodynia was significantly reduced (P=0.003) during painful HTS, as compared to non-painful HTS. In contrast, neither the intensity of brush-evoked allodynia nor the ongoing pain was significantly changed. The results indicate that endogenous pain modulating systems can alter some aspects of chronic neuropathic brush-evoked allodynia. The differential effect of painful HTS on ongoing pain and area of brush-evoked allodynia suggest that separate mechanisms are involved.
Pain 2003 May
PMID:Differential recruitment of endogenous pain inhibitory systems in neuropathic pain patients. 1274 61

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
 ...
PMID:Adenosine in the spinal cord and periphery: release and regulation of pain. 1278 73

Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.
Pain 2003 Jun
PMID:Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain. 1279 33

Neuronal L-type calcium channels have been implicated in pain perception and neuronal synaptic plasticity. To investigate this we have examined the effect of disrupting the gene encoding the CaV1.3 (alpha 1D) alpha subunit of L-type Ca2+ channels on neurological function, acute nociceptive behavior, and hippocampal synaptic function in mice. CaV1.3 alpha 1 subunit knockout (CaV1.3 alpha 1(-/-)) mice had relatively normal neurological function with the exception of reduced auditory evoked behavioral responses and lower body weight. Baseline thermal and mechanical thresholds were unaltered in these animals. CaV1.3 alpha 1(-/-) mice were also examined for differences in N-methyl-D-aspartate (NMDA) receptor-dependent (100 Hz tetanization for 1 s) and NMDA receptor-independent (200 Hz in 100 microM DL-2-amino-5-phosphopentanoic acid) long-term potentiation within the CA1 region of the hippocampus. Both NMDA receptor-dependent and NMDA receptor-independent forms of long-term potentiation were expressed normally. Radioligand binding studies revealed that the density of (+)[3H]isradipine binding sites in brain homogenates was reduced by 20-25% in CaV1.3 alpha 1(-/-) mice, without any detectable change in CaV1.2 (alpha 1C) protein levels as detected using Western blot analysis. Taken together these data indicate that following loss of CaV1.3 alpha 1 subunit expression there is sufficient residual activity of other Ca2+ channel subtypes to support NMDA receptor-independent long-term potentiation and some forms of sensory behavior/function.
 ...
PMID:Neurological phenotype and synaptic function in mice lacking the CaV1.3 alpha subunit of neuronal L-type voltage-dependent Ca2+ channels. 1289 May 13

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.
 ...
PMID:KCNQ/M currents in sensory neurons: significance for pain therapy. 1290 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>