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)

Voltage-gated sodium channels in nociceptive neurons are attractive targets for novel pain therapeutics. Although drugs that target voltage-gated sodium channels have proven value as pain therapeutics, the drugs that are currently available are non-specific sodium channel inhibitors, which limit their usefulness. Recently, a selective small-molecule inhibitor of Na(v)1.8, a voltage-gated sodium channel isoform that participates in peripheral pain mechanisms, has been developed. This exciting new compound shows efficacy in several animal models of pain and is anticipated to be only the first of many new isoform-specific sodium channel blockers.
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PMID:Painful research: identification of a small-molecule inhibitor that selectively targets Nav1.8 sodium channels. 1782 38

Recent scientific advances have enhanced our understanding of the role voltage-gated sodium channels play in pain sensation. Human data on Nav1.7 show that gain-of-function mutations lead to enhanced pain while loss-of-function mutations lead to Congenital Indifference to Pain. Pre-clinical data from knockouts, anti-sense oligonucleotides, and siRNA for Nav1.3, 1.7, 1.8, and 1.9 have also demonstrated that specific subtypes of voltage-gated sodium channels play a role in different types of pain signaling. In addition, recent reports show that CNS penetration by voltage-gated sodium channel blockers is not required for efficacy in pre-clinical pain models while others have reported that identification of subtype-selective small molecules is possible. All of these data are converging to suggest next generation sodium channel blockers may offer the potential for novel pain therapies in the future.
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PMID:Sodium channels and nociception: recent concepts and therapeutic opportunities. 1796 52

Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
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PMID:Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain. 1817 98

Part of the interindividual variability in pain therapy has been associated with genetic polymorphisms. Several genetic variants prevent or at least decrease pain in their carriers as compared with carriers of the respective wild-type or common alleles by impeding the generation, transmission and processing of nociceptive information or by increasing the local availability of active analgesics or their pharmacodynamic effects. Complete prevention of pain has so far been seen in six distinct rare hereditary syndromes, namely the 'channelopathy-associated insensitivity to pain', caused by 13 currently identified variants in the SCN9A gene coding for the alpha-subunit of the voltage-gated sodium channel, and five maladies belonging to the hereditary sensory and autonomic neuropathy (HSAN) I-V syndromes, caused by various mutations in several genes. Reduced pain in the average population has been associated with frequent variants in the micro-opioid receptor gene (OPRM1), catechol-O-methyltransferase gene (COMT), guanosine triphosphate cyclohydrolase 1/dopa-responsive dystonia gene (GCH1), transient receptor potential cation channel, subfamily V, member 1 gene (TRPV1) or the melanocortin-1 receptor gene (MC1R). Duplications/amplifications of the cytochrome P450 2D6 (CYP2D6) gene leading to increased enzyme function may cause intense opioid effects of codeine up to toxicity. The COMT V158M variant has been associated with decreased morphine requirements for analgesia. Inactivating MC1R variants have been associated with increased opioid analgesia of the micro-opioid receptor agonist morphine-6-glucuronide and, in women only, of kappa-opioid agonists. Finally, variants in the P-glycoprotein gene (ABCB1) conferring decreased transporter function have been associated with increased respiratory depressive effects of fentanyl. In summary, a finite number of genetic variants that prevent pain by decreasing nociception or increasing analgesia have been identified. Given the complex biological and psychological nature of pain, we will see in the near future how much of the interindividual variance in pain and analgesia is due to identifiable genetic causes, and to what extent genetics enters clinical pain therapy.
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PMID:Genetic mutations that prevent pain: implications for future pain medication. 1837 Aug 47

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
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PMID:Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain. 1850 13

The Na(V)1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform plays a critical role in nociception. In rodent models of diabetic neuropathy, increased Na(V)1.7 in dorsal root ganglia (DRG) neurons correlates with the emergence of pain-related behaviors characteristic of painful diabetic neuropathy (PDN). We examined the effect of transgene-mediated expression of enkephalin on pain-related behaviors and their biochemical correlates in DRG neurons. Transfection of DRG neurons by subcutaneous inoculation of a herpes simplex virus-based vector expressing proenkephalin reversed nocisponsive behavioral responses to heat, cold, and mechanical pressure characteristic of PDN. Vector-mediated enkephalin production in vivo prevented the increase in DRG Na(V)1.7 observed in PDN, an effect that correlated with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC). Primary DRG neurons in vitro exposed to 45 mm glucose for 18 h also demonstrated an increase in Na(V)1.7 and increased phosphorylation of p38 and PKC; these changes were prevented by transfection in vitro with the enkephalin-expressing vector. The effect of hyperglycemia on Na(V)1.7 production in vitro was mimicked by exposure to PMA and blocked by the myristolated PKC inhibitor 20-28 or the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]; the effect of vector-mediated enkephalin on Na(V)1.7 levels was prevented by naltrindole. The results of these studies suggest that activation of the presynaptic delta-opioid receptor by enkephalin prevents the increase in neuronal Na(V)1.7 in DRG through inhibition of PKC and p38. These results establish a novel interaction between the delta-opioid receptor and voltage-gated sodium channels.
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PMID:Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. 1857 38

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.
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PMID:Mechanisms of cold pain. 1869 33

Tetrodotoxin (TTX)-resistant sodium channels are found in small diameter primary sensory neurons and are thought to be important in the maintenance of inflammatory pain. Here we examined bladder urodynamics of Nav1.9 voltage-gated sodium channel knock out (KO) mice, and the contribution of Nav1.9 to the development of inflammation-based bladder dysfunction. Basal urodynamics were not different between wildtype (WT) mice and those lacking Nav1.9. Peripheral nerve recordings from pelvic afferents in Nav1.9 KO mice revealed a lack of sensitization to intravesicularly applied prostaglandin E2 (PGE2). Consistent with this, cyclophosphamide treatment in vivo, which is associated with an enhancement of PGE2 production, evoked a reduction in bladder capacity of WT, but not Nav1.9 KO mice. We conclude that the Nav1.9 sodium channel provides an important link between inflammatory processes and changes in urodynamic properties that occur during urinary bladder inflammation.
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PMID:The voltage-gated sodium channel Nav1.9 is required for inflammation-based urinary bladder dysfunction. 1914 22

SCN9A, the gene which encodes voltage-gated sodium channel Na(v)1.7, is located on human chromosome 2 within a cluster of other members of this gene family. Na(v)1.7 is present at high levels in most peripheral nociceptive neurons in dorsal root ganglion (DRG) and in sympathetic neurons. In addition to its focal tissue-specific expression, Na(v)1.7 is distinguished by its ability to amplify small depolarizations, thus acting as a threshold channel and modulating excitability. Dominantly inherited gain-of-function mutations in SCN9A have been linked to two familial painful disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). One set of mutations leads to severe episodes of pain in the feet and hands in patients with IEM, and a different set of mutations causes pain in a perirectal, periocular, and mandibular distribution in patients with PEPD. These mutations allow mutant channels to activate in response to weaker stimuli, or to remain open longer in response to stimulation. The introduction of mutant channels into DRG neurons alters electrogenesis and renders these primary sensory neurons hyperexcitable. Mutant Na(v)1.7 channels lower the threshold for single action potentials and increase the number of action potentials that neurons fire in response to suprathreshold stimuli. In contrast, recessively inherited loss-of-function mutations in SCN9A, which cause a loss of function of Na(v)1.7 in patients, lead to indifference to pain with sparing of motor and cognitive abilities. The central role of Na(v)1.7 in these disorders, and the apparently limited consequences of loss of this channel in humans make it an attractive target for treatment of pain.
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PMID:Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes. 1918 86

Eugenol is widely used in dentistry as a local analgesic agent, because of its ability to allay tooth pain. Interestingly, eugenol shares several pharmacological actions with local anesthetics which include inhibition of voltage-gated sodium channel (VGSC) and activation of transient receptor potential vanilloid subtype 1 (TRPV1). In the present study, we investigated the effects of eugenol on pain behaviors in orofacial area, and as an attempt to elucidate its mechanism we characterized inhibitory effects of eugenol on VGSCs in trigeminal ganglion (TG) neurons. TG neurons were classified into four types on the basis of their neurochemical and electrophysiological properties such as cell size, shapes of action potential (AP), isolectin-B(4) (IB(4)) binding, and were analyzed for the association of their distinctive electrophysiological properties and mRNA expression of Na(v)1.8 and TRPV1 by using single-cell RT-PCR following whole-cell recordings. Subcutaneous injection of eugenol reduced the thermal nociception and capsaicin-induced thermal hyperalgesia in a dose-dependent manner. Eugenol also diminished digastric electromyogram evoked by noxious electrical stimulation to anterior tooth pulp, which was attributable to the blockade of AP conduction on inferior alveolar nerve. At cellular level, eugenol reversibly inhibited APs and VGSCs in IB(4)+/TRPV1+/Na(v)1.8+ nociceptive TG neurons (Type I-Type III) and IB(4)-/TRPV1-/Na(v)1.8- nociceptive TG neurons (Type IV). Both TTX-resistant I(Na) in Type I-Type III neurons and TTX-sensitive I(Na) in Type IV neurons were sensitive to eugenol. Taken together, these results suggest that eugenol may serve as local anesthetics for other pathological pain conditions in addition to its wide use in dental clinic.
Pain 2009 Jul
PMID:Molecular mechanism for local anesthetic action of eugenol in the rat trigeminal system. 1937 53


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