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)

The aim of this study is to evaluate operative treatment of hallux valgus deformity at the Department of Orthopedic surgery, Zagreb School of Medicine, and present our protocol for the management of hallux valgus deformity. In the time period from 1981 to 2000 operative procedures for hallux valgus deformity were performed on 1211 feet in 820 patients (788 females and 32 males). Criteria for operative treatment were: increased hallux valgus angle (HVA), increased first intermetatarsal angle (IMTA), first metatarsophalangeal joint arthritis, pain and cosmetic reasons. Radiographic observations as well as clinical and subjective evaluation were made preoperatively and after the surgery. Observations were classified using Helal's modification of Boney and McNab classification. Resection of the proximal end of the proximal phalanx was performed in 250 patients (402 feet) with 55% of excellent results (221 patients over 60 years of age). Distal first metatarsal Austin osteotomy was performed in 312 patients (429 feet) with 49% of excellent results (210 feet, mean patient age 50 years, mean HVA 27 degrees, mean IMTA 15 degrees). Distal first metatarsal Mitchell osteotomy was performed in 230 patients (380 feet) with 40% of excellent results (152 feet, mean patient age 24 years, mean HVA 26 degrees, mean IMTA 15 degrees). Our experience in the operative treatment of hallux valgus deformity suggests that in order to achieve excellent results after surgery, strict criteria for each operative method must be applied.
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PMID:[Surgical treatment of hallux valgus deformity at the Department of Orthopaedic Surgery, Zagreb School of Medicine, in the period 1981-2000]. 1858 36

Ion channels are often modulated by intracellular calcium levels. TRPV1, a channel responsible for the burning pain sensation in response to heat, acid or capsaicin, is desensitized at high intracellular calcium concentrations. We recently identified a multiligand-binding site in the N-terminal ankyrin repeat domain (ARD) of TRPV1 that binds ATP and sensitizes the channel. Calcium-calmodulin binds the same site and is necessary for calcium-mediated TRPV1 desensitization. Here, we examine in more detail the conservation of this TRPV1 multiligand-binding site in other species. Furthermore, using sequence analysis, we determine that the unusually twisted shape of the TRPV1-ARD is likely conserved in other TRPV channels, but not in the ARDs of other TRP subfamilies.
Channels (Austin)
PMID:Insights into the roles of conserved and divergent residues in the ankyrin repeats of TRPV ion channels. 1869 26

Sodium channels are key proteins in regulating neuronal excitability and accumulating data suggest that specific subtypes of voltage-dependent sodium channels are important in signaling various types of pain. Consistent with this theme, Jarvis et al.(7) recently reported the identification of a subtype-selective Na(v)1.8 blocker that was active in several pre-clinical models of pain. During the course of these studies compounds were also identified that showed large differences in potency when tested on Na(v)1.8 channels from different species. This addendum illustrates one of these compounds along with the potency correlation between recombinant and native tetrodotoxin-resistant sodium channels for additional examples. These data show that significant differences can be observed for sodium channel blockers across species and highlight the importance of considering this possibility when searching for new compounds and research tools to probe sodium channel function.
Channels (Austin)
PMID:Block of Nav1.8 by small molecules. 1869 30

Avoidance of cold pain is an important survival mechanism. Intriguingly, whilst cooling can cause numbness, damage sensing mechanisms still seem to operate at low temperatures, and pain can be perceived from cooled damaged tissue. Recent studies have identified two cold-activated transient receptor potential (TRP) channels present in sensory neurons as transducers of cold stimuli. TRPM8 seems to mediate responses to cooling whilst TRPA1 is activated, possibly indirectly, by more extreme cold conditions. The existence of cold-responsive neurons that do not express these channels suggests that other transducers of cold stimuli remain to be discovered. Subsequent action potential electrogenesis and probably propagation from sensory neurons innervating cold tissues depends upon the presence of Na(v)1.8, the sole voltage-gated sodium channel that fails to inactivate at low temperatures. This may explain the remarkable specificity of Na(v)1.8 expression in nociceptive neurons, where it plays an important role in pain pathways.
Channels (Austin)
PMID:Mechanisms of cold pain. 1869 33

Antiarrhythmics, anticonvulsants and local anesthetics inhibit voltage-gated sodium channels and reduce membrane excitability in neurons and muscle, making them useful in the management of cardiac arrhythmias, epilepsy and pain. These compounds, which are often termed singly in the literature as 'local anesthetics', have at least two inhibitory states: a resting inhibition that develops with intermittent stimulation and a higher affinity inhibition that arises upon repeated depolarization and likely involves the inactivated state of the channel. Although elucidating their mechanism of inhibition has been an active area of research for decades, many questions remain unanswered. Do these two inhibitory states share a common, but guarded or modulated receptor? Or do they represent different protonated states of the drugs, many of which have pKa's close to physiological pH, thereby yielding a significant population of both charged and uncharged compound inside cells. Some mechanistic clues can be found by mutating conserved phenylalanine and tyrosine residues of the 'local anesthetic receptor' in the channel's inner vestibule. Mutations of these aromatic residues universally disrupt the mechanism of drug inhibition in numerous channel isoforms. For instance, non aromatic substitutions of Phe1579 (Na(V) numbering) in the pore lining S6 segment of domain four (DIVS6) can abolish inactivated state inhibition.(1,2) The strict conservation of Phe1579 and other DIVS6 aromatic residues in all nine sodium channel isoforms led us to further dissect the role of this and other aromatic residues on local anesthetic inhibition. We recently employed subtly modified phenylalanine derivatives to better understand the role of these aromatics in the binding of local anesthetics and found a significant electrostatic interaction at one site, Phe1579, contributes to channel inhibition.(3) What follows is a self guided tour of our motivation and experimental findings.
Channels (Austin)
PMID:New insights into the therapeutic inhibition of voltage-gated sodium channels. 1869 56

T-type calcium channels are involved in the generation of rhythmical firing patterns in the mammalian central nervous system and in various pathological alterations of neuronal excitability such as in epilepsy or neuropathic pain. In the search for new T-type calcium channel blockers that would help to treat these disorders, we have followed a bi-dimensional pharmacophore-based virtual screening approach to identify new inhibitors. Nineteen molecules extracted from AurSCOPE Ion Channels knowledgebase were used as query molecules to screen an external database. This in silico approach was then validated using electrophysiology. Interestingly, 16 compounds out of 38 distinct molecules tested showed more than 50% blockade of the Ca(V)3.2 mediated T-type current. Two series of compounds show chemical originality compared with known T-type calcium channel blockers.
Channels (Austin)
PMID:Ligand-based virtual screening to identify new T-type calcium channel blockers. 1870 47

Recent evidence strongly suggests that both central and peripheral T-type Ca(2+) channels enhance somatic and visceral nociceptive inputs, as well as that regulation of T-type Ca(2+) channel function can result in significant changes of pain threshold in a variety of animal models. Therefore, T-type Ca(2+) channels in peripheral and central pain pathways, although previously unrecognized, may have great importance as targets for developing new therapies against pain. This is particularly critical in cases in which currently available treatments are limited due to serious side effects or are not consistently effective (e.g., chronic neuropathic pain). In this review, we summarize recent studies of the regulation of T-type channels in peripheral sensory neurons by means of redox agents and neuroactive steroids, as well as studies of the function of these channels in the pathophysiology of neuropathic pain.
Channels (Austin)
PMID:Regulation of T-type calcium channels in the peripheral pain pathway. 1870 51

TRPA1 is a member of the transient receptor potential (TRP) cation channel family, and is predominantly expressed in nociceptive neurons of dorsal root ganglia (DRG) and trigeminal ganglia. Activation of TRPA1 by environmental irritants such as mustard oil, allicin and acrolein causes acute pain. However, the endogenous ligands that directly activate TRPA1 remain elusive in inflammation. Here, we show that a variety of inflammatory mediators (15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), nitric oxide (NO), hydrogen peroxide (H(2)O(2)), and proton (H(+))) activate human TRPA1 heterologously expressed in HEK cells. These inflammatory mediators induced robust Ca(2+) influx in a subset of mouse DRG neurons. The TRP channel blocker ruthenium red almost completely inhibited neuronal responses by 15d-PGJ(2) and NO, but partially suppressed responses to H(2)O(2) and H(+). Functional characterization of site-directed cysteine mutants of TRPA1 in combination with labeling experiments using biotinylated 15d-PGJ(2) demonstrated that modifications of cytoplasmic N-terminal cysteines (Cys421 and Cys621) were responsible for the activation of TRPA1 by 15d-PGJ(2). In TRPA1 responses to other cysteine-reactive inflammatory mediators, such as NO and H(2)O(2), the extent of impairment by respective cysteine mutations differed from those in TRPA1 responses to 15d-PGJ(2). Interestingly, the Cys421 mutation critically impaired the TRPA1 response to H(+) as well. Our findings suggest that TRPA1 channels are targeted by an array of inflammatory mediators to elicit inflammatory pain in the nervous system.
Channels (Austin)
PMID:Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. 1876 39

Conus peptides that are selectively targeted to different molecular isoforms of nicotinic acetylcholine receptors (nAChRs) have been identified and characterized; several have recently been shown to have significant biomedical potential. An emerging strategy for the discovery from animal biodiversity of subtype-specific ligands for ion channel families is described in this review. Characterization of the gene family encoding a set of related ligands is required for discovery using a molecular genetics approach; when discovery is guided by a knowledge of the phylogeny of the biodiverse animal lineage being used as a source of ligands, a rational, efficient scan of the library of putative ligands becomes feasible. Together, these constitute an approach to uncover subtype-specific ligands, called "concerted discovery"; this was applied to the alpha-conotoxins, a family of Conus peptides generally targeted to nAChRs. Subtype-specific alpha-conotoxins were developed that target two groups of nAChRs, alpha(6)* and alpha(9)*. alpha-conotoxin MII has become the defining ligand for identifying the alpha(6)* nAChR subtype. A synthetic analog, MII [E11A], further subdivides alpha(6)* nAChRs into those that contain an alpha(4) subunit and those that do not. Importantly, these two subtypes are differentially affected by nigrostriatal damage, findings of likely relevance to the pathopysiology of Parkinson's disease. In contrast, alpha-conotoxins that target alpha(9) nAChR subtypes have potential as analgesics for the treatment of neuropathic pain that develops after nerve injury. The discovery of alpha-conotoxin RgIA enabled the identification of a novel role for alpha(9)* nAChRs. Use of alpha(9)* nAChR antagonists is associated with reversal of inflammation caused by the nerve injury. Thus, subtype-specific alpha-conotoxins targeted to particular nAChR isoforms are not only useful for understanding the physiological role of these receptors, but can have important diagnostic and therapeutic applications as well.
Channels (Austin)
PMID:Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications. 1884 60

Evidence supports a role for the tetrodotoxin-sensitive Na(V)1.7 and the tetrodotoxin-resistant Na(V)1.8 in the pathogenesis of pain. Ranolazine, an anti-ischemic drug, has been shown to block cardiac (Na(V)1.5) late sodium current (I(Na)). In this study, whole-cell patch-clamp techniques were used to determine the effects of ranolazine on human Na(V)1.7 (hNa(V)1.7 + beta(1) subunits) and rat Na(V)1.8 (rNa(V)1.8) channels expressed in HEK293 and ND7-23 cells, respectively. Ranolazine reduced hNa(V)1.7 and rNa(V)1.8 I(Na) with IC50 values of 10.3 and 21.5 microM (holding potential = -120 or -100 mV, respectively). The potency of I(Na) block by ranolazine increased to 3.2 and 4.3 microM when 5-sec depolarizing prepulses to -70 (hNa(V)1.7) and -40 (rNa(V)1.8) mV were applied. Ranolazine caused a preferential hyperpolarizing shift of the steady-state fast, intermediate and slow inactivation of hNa(V)1.7 and intermediate and slow inactivation of rNa(V)1.8, suggesting preferential interaction of the drug with the inactivated states of both channels. Ranolazine (30 microM) caused a use-dependent block (10-msec pulses at 1, 2 and 5 Hz) of hNa(V)1.7 and rNa(V)1.8 I(Na) and significantly accelerated the onset of, and slowed the recovery from inactivation, of both channels. An increase of depolarizing pulse duration from 3 to 200 msec did not affect the use-dependent block of I(Na) by 100 microM ranolazine. Taken together, the data suggest that ranolazine blocks the open state and may interact with the inactivated states of Na(V)1.7 and Na(V)1.8 channels. The state-and use-dependent modulation of hNa(V)1.7 and rNa(V)1.8 Na+ channels by ranolazine could lead to an increased effect of the drug at high firing frequencies, as in injured neurons.
Channels (Austin)
PMID:Block of tetrodotoxin-sensitive, Na(V)1.7 and tetrodotoxin-resistant, Na(V)1.8, Na+ channels by ranolazine. 1907 43


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