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

Human dorsal root ganglia (DRGs) were obtained during various procedures and processed for single and double in situ hybridisation using oligonucleotide probes complementary to three peptide mRNAs. Some postmortem ganglia were also analysed. In donor (unlesioned) DRGs 12.5% of the neuron profiles (NPs) were galanin mRNA-positive (mRNA(+)), 47.5% calcitonin gene-related peptide (CGRP) mRNA(+) and 32.7% substance P mRNA(+). The corresponding percentages for cervical/thoracic DRGs from patients suffering from severe brachial plexus injury were 32.8%, 57.4% and 34.5%, respectively. In these DRGs a high proportion of the galanin mRNA(+) NPs contained CGRP mRNA and substance P mRNA. In DRGs from a patient with migraine-like pain a comparatively small proportion expressed galanin, whereas in DRGs from a herpes zoster patient galanin mRNA(+) NPs were comparatively more frequent. The results from human postmortem DRGs revealed only weak peptide mRNA signals. The present results demonstrate that galanin is expressed in DRGs not only in a number of animal species including monkey as previously shown, but also in a considerable proportion of human DRG neurons, often together with CGRP and substance P, and mostly in small neurons. Thus, galanin may play a role in processing of sensory information, especially pain, in human DRGs and dorsal horn. However, to what extent a similarly dramatic upregulation of galanin expression can be seen after peripheral nerve lesion in man, as has been reported for rat, mouse and monkey, remains to be analysed.
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PMID:Galanin expression in adult human dorsal root ganglion neurons: initial observations. 1265 33

Acid sensing ion channel 3 (ASIC3) is a cation channel gated by extracellular protons. It is highly expressed in sensory neurons, including small nociceptive neurons and has been proposed to participate in pain perception associated with tissue acidosis and in mechanoperception. Neuropeptide FF (NPFF) and FMRFamide have been shown to potentiate proton-gated currents from cultured sensory neurons and acid sensing ion channel (ASIC) cDNA transfected cells. In this study, we report that another mammalian peptide neuropeptide SF (NPSF), derived from the same precursor, also considerably increases the amplitude of the sustained current of heterologously expressed ASIC3 (12-fold vs. 19- and nine-fold for FMRFamide and NPFF, respectively) with an EC(50) of approximately 50 microM. Similar effects were also observed on endogenous ASIC3-like sustained current recorded from DRG neurons although of smaller amplitudes (two-, three- and seven-fold increase for NPSF, NPFF and FMRFamide, respectively), and essentially related to a slowing down of the inactivation rate. Importantly, this modulation induced changes in neuronal excitability in response to an electrical stimulus applied during extracellular acidification. ASIC3-mediated sustained depolarisation, and its regulation by neuropeptides, could thus be important in regulating polymodal neuron excitability particularly under inflammatory conditions where the expression levels of both NPFF precursor and ASIC3 are increased.
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PMID:Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. 1266 52

Tumor necrosis factor-alpha (TNF) is implicated in the initiation of neuropathic pain. In vitro, TNF activates p38 mitogen-activated kinase. Accordingly, we investigated whether TNF activates the p38 cascade in vivo to trigger pain behavior after spinal nerve ligation (SNL). Treatment starting 2 d before SNL with the TNF antagonist etanercept (1 mg, i.p., every third day) attenuated mechanical allodynia. Treatment starting 1 or 7 d after SNL was ineffective. Similarly, intrathecal infusion of a p38 inhibitor (SB203580, 4 mg/d) was effective only if it was started before but not 7 d after SNL. For both treatments, the cessation of therapy resulted in increased allodynia. In separate experiments using Western blots and immunohistochemistry, ipsilateral lumbar spinal cord and L5 and L6 DRG were analyzed for total and phosphorylated p38 after SNL alone or SNL combined with etanercept pretreatment. In DRG, activated p38 was transiently elevated 5 hr after SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38 was activated between 5 hr and 3 d after SNL and returned to baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL treatment, phosphorylated p38 levels in spinal cord and DRG are transiently elevated. In DRG, p38 activation is blocked by systemic TNF inhibition. Parallel inhibition of p38 activation and allodynia may represent a clinically relevant therapeutic window. These data suggest a sequential role for TNF and p38 in the induction of neuropathic pain.
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PMID:Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. 1268 35

To develop a genetic approach for the treatment of pain, we introduced a recombinant adeno-associated viral (rAAV) vector containing the cDNA for the mu-opioid receptor (muOR) into primary afferent neurons in dorsal root ganglia (DRGs) of rats, which resulted in a long-lasting (>6 months) increase in muOR expression in DRG neurons. The increase greatly potentiated the antinociceptive effects of morphine in rAAV-muOR-infected rats with and without inflammation. Perforated patch recordings indicated that the efficacy and potency of opioid inhibition of voltage-dependent Ca(2+) channels were enhanced in infected neurons, which may underlie the increase in opiate efficacy. These data suggest that transfer of opioid receptor genes into DRG cells with rAAV vectors may offer a new therapeutic strategy for pain management.
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PMID:Adeno-associated viral transfer of opioid receptor gene to primary sensory neurons: a strategy to increase opioid antinociception. 1271 38

The capsaicin receptor transient receptor potential V1 (TRPV1; also known as vanilloid receptor 1) is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that extracellular ATP potentiates the TRPV1 currents evoked by capsaicin or protons and reduces the temperature threshold for its activation through metabotropic P2Y receptors in a PKC-dependent pathway, suggesting that TRPV1 activation could trigger the sensation of pain at normal body temperature in the presence of ATP. Here, we show that ATP-induced thermal hyperalgesia was abolished in mice lacking TRPV1, suggesting the functional interaction between ATP and TRPV1 at a behavioral level. However, thermal hyperalgesia was preserved in P2Y1 receptor-deficient mice. Patch-clamp analyses using mouse dorsal root ganglion neurons indicated the involvement of P2Y2 rather than P2Y1 receptors. Coexpression of TRPV1 mRNA with P2Y2 mRNA, but not P2Y1 mRNA, was determined in the rat lumbar DRG using in situ hybridization histochemistry. These data indicate the importance of metabotropic P2Y2 receptors in nociception through TRPV1.
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PMID:Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity. 1285 24

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.
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PMID:KCNQ/M currents in sensory neurons: significance for pain therapy. 1290 83

In conclusion, the nerve roots and the DRG play an important role in the pain mechanisms of patients suffering from chronic low back pain. Signs of demyelination and increased sensitization for stimuli occurs after a direct nerve root trauma, and the plasticity for the DRG also may change the response to a given peripheral stimuli when repeated frequently over a long period of time. The regeneration mechanisms of spinal nerve roots and DRG regarding function are slow, and the final grade of recurrence depends on the degree of injury. The limited regeneration mechanisms for nerve injury and the fact that "established chronic pain centers" are hard to influence after a long pain history favor an aggressive strategy for pain management. Today, a number of treatment strategies exist for chronic low back pain patients (with or without a diagnosed nerve root injury). These strategies include physiotherapy, nonsteroid anti-inflammatory drugs (NSAIDs), steroids, analgesics of different types and administration routes, surgery, and other sorts of invasive treatments. Further knowledge about the nerve root, DRG, and the rest of the nervous system in these patients is necessary; for understanding how and when to treat patients with chronic low back pain, we need to understand more about what we are trying to treat.
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PMID:Nerve root injuries in patients with chronic low back pain. 1291 61

The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro-inflammatory cytokines, leading in turn to sensitization. Macrophages also express alpha2-adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri-neural injection of the alpha2-adrenoceptor agonist, clonidine, in rats with chronic nerve injury. The current study tested whether peri-neural clonidine at the time of injury could also prevent development of hypersensitivity. Rats underwent partial ligation of one sciatic nerve, and peri-neural saline, clonidine or a combination of clonidine and the alpha2A-adrenceptor-preferring antagonist, BRL44408, were administered before wound closure and, in some animals, also 24 and 48 h later. The single clonidine injection reduced hypersensitivity for only 5 h, whereas repeated injection for three days reduced hypersensitivity for 28 days. Peri-neural clonidine reduced the increase in tissue content of the proinflammatory cytokines IL-1beta and particularly TNFalpha in sciatic nerve, DRG and spinal cord while increasing concentrations of the anti-inflammatory cytokine TGF-beta1. Clonidine's effects on behavior and TNFalpha content were blocked by BRL44408. We conclude that peri-neural administration of clonidine at the site and time of injury reduces the degree of hypersensitivity in part by altering the balance of pro- and anti-inflammatory cytokines through activation of alpha2A-adrenoceptors. These results support testing of whether clonidine, as an adjuvant in continuous peripheral nerve blocks in settings of known major nerve injury, such as limb amputation, might prevent the development of chronic pain.
Pain 2003 Sep
PMID:Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. 1449 42

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.
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PMID:Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain. 1458 Nov 79

The aim of this study was to check the clinical predictive variables of the variance of the total cost by GHM for patients undergoing chemotherapy. 10 different hospitals registered 537 hospital stays and 1,535 day care sessions. The initial disease, metastases, other pathologies, participation to randomised trial were recorded. Each day health status, pain, stage of the protocol and the drugs, use of catheter, pump or chamber implant were noted. Work was measured separately for physicians and nurses per 24 hours using a visual analogy scale. Lab tests and drugs were recorded for each patient. The cost of the drugs explain 98% of the variance of the total cost for the day care and 50% for the hospitalisations. For the latter, beside the cost of drugs, the length of stay, labor, initial disease, age, pain and associated pathology are predictive variables. According to this results, we conclude that the drugs for chemotherapy should be paid separately. No other change should be made for day care. DRG for hospitalized patients should take into account initial disease, age and pain.
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PMID:[Refining the French system of cost assessment for oncology patients following chemotherapy]. 1470 3


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