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)

Symptoms of FMS are extremely distressing, and currently there is no cure or any treatment capable of substantially reducing all symptoms for all patients. Rehabilitation goals include improving emotional functioning, physical functioning, and quality of life. In light of these goals, psychological screening is an essential component of any comprehensive FMS evaluation. In many cases, the high levels of emotional distress, disability, and reduced quality of life noted in these patients warrants a more thorough psychological evaluation [11]. A comprehensive psychological evaluation is complex, involves exploration of a broad range of areas, and should be administered by an experienced health psychologist. The primary objective of this evaluation is to delineate emotional, cognitive, and behavioral factors involved in persistent pain, suffering, and disability, with an emphasis on the prescription of appropriate interventions for altering maladaptive patterns. The results of the psychological evaluation involve a synthesis of information and should assist in developing a list of behavioral problems that contribute to the maintenance and exacerbation of [table: see text] suffering and disability. Information obtained should facilitate treatment planning, specifically the matching of treatment components to the needs of individual patients.
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PMID:Psychological evaluation of patients diagnosed with fibromyalgia syndrome: a comprehensive approach. 1212 15

As demonstrated above, the anatomy and neuropharmacology of the pain pathways within the CNS, even to the level of the midbrain, are extraordinarily complex. Indeed, discussions of the effects of these agents on the neuropharmacology of the thalamus, hypothalamus, and cortex were excluded from this review owing to their adding further to this complexity. Also, the dearth of data regarding FMS pain pathophysiology necessitated a relatively generic analysis of the pain pathways. As mentioned in the introduction, the current thought is that central sensitization plays an important role in FMS. However, we see in this chapter that the behavioral state of central sensitization may be a result of alterations in either the ascending systems or in one or more descending systems. Studies to assess the presence or relative importance of such changes in FMS are difficult to perform in humans, and to date there are no animal models of FMS. Accepting these limitations, it is apparent that many drugs considered to date for the treatment of FMS do target a number of appropriate sites within both the ascending and descending pain pathways. The data regarding clinical efficacy on some good candidate agents, however, is extremely preliminary. For example, it is evident from the present analysis that SNRIs, alpha 2 agonists, and NK1 antagonists may be particularly well suited to FMS, although current data supporting their use is either anecdotal or from open-label trials [114,149]. Other sites within the pain pathways have not yet been targeted. Examples of these include the use of CCKB antagonists to block on-cell activation or of nitric oxide synthetase antagonists to block the downstream mediators of NMDA activation. Efficacy of such agents may give considerable insight into the pathophysiology of FMS. Finally, as indicated previously, FMS consists of more than just chronic pain, and the question of how sleep abnormalities, depression, fatigues, and so forth tie into disordered pain processing is being researched actively. Future research focusing on how the various manifestations of FMS relate to one another undoubtedly will lead to a more rational targeting of drugs in this complex disorder.
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PMID:The neuropharmacology of centrally-acting analgesic medications in fibromyalgia. 1212 16

Alteration in the intracellular signal transduction pathway in primary afferent neurons may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of extracellular signal-regulated protein kinases (pERK) occurred in DRG neurons that were taking part in the transmission of various noxious signals. The electrical stimulation of Adelta fibers induced pERK primarily in neurons with myelinated fibers. c-Fiber activation by capsaicin injection induced pERK in small neurons with unmyelinated fibers containing vanilloid receptor-1 (VR-1), suggesting that pERK labeling in DRG neurons is modality specific. Electrical stimulation at the c-fiber level with different intensities and frequencies revealed that phosphorylation of ERK is dependent on the frequency. We examined the pERK in the DRG after application of natural noxious stimuli and found a stimulus intensity-dependent increase in labeled cell size and in the number of activated neurons in the c- and Adelta-fiber population. Immunohistochemical double labeling with phosphorylated ERK/VR-1 and pharmacological study demonstrated that noxious heat stimulation induced pERK in primary afferents in a VR-1-dependent manner. Capsaicin injection into the skin also increased pERK labeling significantly in peripheral fibers and terminals in the skin, which was prevented by a mitogen-activated protein kinase/ERK kinase inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminopheylthio)butadiene (U0126). Behavioral experiments showed that U0126 dose-dependently attenuated thermal hyperalgesia after capsaicin injection and suggested that the activation of ERK pathways in primary afferent neurons is involved in the sensitization of primary afferent neurons. Thus, pERK in primary afferents by noxious stimulation in vivo showed distinct characteristics of expression and may be correlated with the functional activity of primary afferent neurons.
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PMID:Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. 1219 97

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.
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PMID:No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V. 1260 14

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).
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PMID:Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. 1223 19

We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat-induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre-drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A-delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap-induced windup when compared with age- and sex-matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A-delta-nociceptive afferent input. Heat and cold-induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 microg/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations.
Pain 2002 Sep
PMID:Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. 1223 83

We reviewed 18 patients (knees) operated on because of chronic PCL insufficiency. Preoperatively all the patients were severely disabled and showed a posterior drawer of 10 mm or more. A quadriceps tendon autograft was implanted using an open technique, direct posterior approach, and fixation to the tibia. A free semitendinosus graft was used to reconstruct the lateral collateral ligament in six knees and the medial collateral ligament in two. The patients were reviewed with a mean follow-up of 3.5 years (range 2-5.5) using the IKDC form. Stability was evaluated by stress radiography using the Telos device. The mean side-to-side difference in posterior tibial displacement at 70 degrees of knee flexion at follow-up was 4.8 mm; the side-to-side difference was less than 5 mm in 77% of cases. A side-to-side difference less than 2 mm in lateral joint line opening was found in five of six knees with a lateral collateral ligament reconstruction. Posterior tibial translation was similar in the knees with and those without collateral ligament reconstruction. Only one patient complained of significant pain and giving-way at follow-up. Patellofemoral crepitation was present in nine knees at follow-up although it was symptomatic only in one. The results of this series suggest that posterior cruciate ligament reconstruction using an autologous quadriceps tendon is a valuable option to reconstruct these severe injuries.
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PMID:Posterior cruciate ligament reconstruction with the quadriceps tendon in chronic injuries. 1235 99

Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF) acts as central pain neuromodulator. We examined the ability of different types of peripheral stimulation to activate the BDNF high-affinity receptor, TrkB, in the spinal cord. We found that noxious chemical, mechanical, or thermal stimuli, but not innocuous stimuli, caused Trk phosphorylation in the spinal cord. These changes were rapid and transient and restricted to somatotopically appropriate spinal segments. We observed, both in vitro and in vivo, that exogenous BDNF induced a rapid activation of ERK, a signaling kinase important in the development of acute pain. Finally, we found that sequestering BDNF in vivo with a TrkB-IgG fusion molecule significantly reduced the activation of ERK evoked by noxious stimulation. These data suggest that BDNF, once released with activity from primary afferent nociceptors, exerts a neuromodulatory role in pain processing through stimulation of postsynaptic TrkB receptors and subsequent activation of ERK.
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PMID:Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. 1250

Diffuse noxious inhibitory control (DNIC) is part of a central pain modulatory system that relies on spinal and supraspinal mechanisms. Previous studies have shown that fibromyalgia (FMS) patients are lacking DNIC effects on experimental pain, compared to normal control (NC) subjects. Because DNIC has a greater effect on second pain than on first pain, we hypothesized that wind-up (WU) of second pain should be attenuated by a strong conditioning stimulus. Thus, we compared DNIC's effect on WU in three groups of subjects: 11 NC males, 22 NC females, and 11 FMS females. To separately assess the contributions of distraction related mechanisms to inhibition of second pain, we designed the experiment in such a way that directed the subjects' attention to either the test or conditioning stimulus. Repeated heat taps to the thenar surface of the right hand were used as test stimuli to generate WU of second pain. Immersion of the left hand into a hot water bath was the conditioning stimulus. As previous experiments have shown, DNIC requires a strong conditioning stimulus for pain attenuation, which may be at least partly dependent on a distraction effect. DNIC significantly inhibited thermal WU pain in normal male subjects, but adding distraction to the DNIC effect did not increase the extent of this inhibition. In contrast, neither DNIC nor DNIC plus distraction attenuated thermal WU pain in female NCs. DNIC plus distraction but not DNIC alone produced significant inhibition of thermal WU pain in female FMS patients. Our results indicate that DNIC effects on experimental WU of second pain are gender specific, with women generally lacking this pain-inhibitory mechanism.
Pain 2003 Jan
PMID:Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. 1250 11

RET and NTRK1 are receptor tyrosine kinase (RTK) proteins which play a role in the development and maturation of specific component of the nervous system. Their alterations have been associated to several human diseases, including some forms of cancer and developmental abnormalities. These features have contributed to the concept that one gene can be responsible for more than one disease. Moreover, both genes encoding for the two RTKs show genetic alterations that belong to either "gain of function" or "loss of function" class of mutations. In fact, receptor rearrangements or point mutations convert RET and NTRK1 in dominantly acting transforming genes leading to thyroid tumors, whereas inactivating mutations, associated with Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA), impair RET and NTRK1 functions, respectively. In this review we have summarized the main features of the two receptors, their physiological and pathological roles. In addition, we attempted to identify the correlations between the different genetic alterations and the related pathogenetic mechanisms.
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PMID:RET and NTRK1 proto-oncogenes in human diseases. 1265 44


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