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1.
We studied the voltage- and use-dependent action of pyrrolo-imidazole derivative, D57, on sodium currents in different dorsal root ganglion neurons of rats. At the level of 50% of maximum tonic block, which corresponded to a concentration of 0.44 mM, the use-dependent block of tetrodotoxin resistant (TTXr) sodium currents reached 59 ± 12% of the remaining currents when neurons were stimulated by 6-msec-long impulses up to -10 mV with a 20 sec-1 frequency, whereas for TTX sensitive (TTXs) currents this value was equal to 38 ± 9%. This block was dependent on the holding potential, and for cells with only TTXr currents the dependence was shifted to more positive potentials compared with that for neurons with only TTXs currents or with both of them. 相似文献
2.
Pantellev SS Martseva AA Liubashina OA 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2011,97(12):1336-1345
In experiments on anaesthetized rats, the neuronal mechanisms underlying processing of the nociceptive information from the colon within the nucleus of the solitary tract were studied. In addition, the role of nitric oxide in these processes was estimated. Analysis of changes in c-fos expression revealed that nociceptive colorectal distension (CRD) resulted in activation of neurons mainly in the medial, commissural, parvicellular and dorsomedial subnuclei of the solitary tract nucleus. Non-noxious CRD evoked in these subdivisions weak phasic excitatory neuronal responses. Under noxious CRD, neurons with phasic (58%) and tonic (42%) responses were revealed. The phasic neuron responses were significantly enhanced in comparison with non-noxious CRD. Inhibition of the neuronal NO-syntheses resulted in significant decrease of neuron responses to noxious CRD and the number of cells with tonic reactions. Therefore, neurons with tonic responses may be directly related to NO-depended processing ofnociceptive information from colon. 相似文献
3.
On a model of a thin (C-type) primary afferent fiber, we examined one of the hypotheses related to the phenomenon of initiation
of long-lasting tonic discharges in nociceptive afferents. In the membrane of a region corresponding to the free peripheral
terminal of the modeled nociceptive C fiber, there were sodium channels of three types (channels of rapidly inactivating TTX-sensitive
current and TTX-resistant channels of two types, NaV1.8/SNS/PN3 and NaV1.9/NaN/SNS2). As is known, TTX-resistant sodium currents promote the development of long-lasting trains of action potentials,
APs, where the duration of tonic discharges exceeds by orders of magnitude the duration of short stimuli inducing such discharges.
Such trains, when transmitted to the spinal cord, are interpreted as pain signals. Using the model, we obtained the time course
of changes in the membrane potential in the distal and proximal segments of the nerve fiber and values of the densities of
inward and outward TTX-resistant sodium currents through channels NaV1.9/NaN/SNS2 and NaV1.8/SNS/PN3 in the norm and in a state mimicking the action of inflammation factors. Results of modeling demonstrated that
TTX-resistant sodium currents provide intensification of slow components in the generated APs (plateau afterdepolarization).
Having a higher inactivation threshold, these currents are inactivated more slowly and recover more rapidly after inactivation,
as compared with the currents through TTX-sensitive sodium channels. Such behavior presupposes a considerable role of the
TTX-resistant currents in facilitation of transmission of nociceptive signals under conditions of neuropathic pain characterized
by excessive “upregulation” of the respective channels. It can be concluded that expression of TTX-resistant sodium channels
in nociceptive sensory neurons possessing primary afferent C fibers, the presence of these channels in the membranes of peripheral
terminals of the above fibers, and modification of biophysical properties of such channels under conditions of action of inflammation
mediators, when taken together, create substantial prerequisites for initiation of anomalous long-lasting AP trains in the
above peripheral terminals and, therefore, for transmission of such signals to the CNS. Such a situation appears to be a key
electrophysiological phenomenon responsible for generation of neuropathic and inflammation-related pain. 相似文献
4.
Using whole-cell patch clamp technique on the membrane of freshly isolated dorsal root ganglion (DRG) neurons, the effects
of dragon’s blood resin and its important component loureirin B on tetrodotoxin-sensitive (TTX-S) voltage-gated sodium currents
were observed. The results show that both blood resin and loureirin B could suppress TTX-S voltage-gated sodium currents in
a dose-dependent way. The peak current amplitudes and the steady-state activation and inactivation curves are also made to
shift by 0.05% blood resin and 0.2 mmol/L loureirin B. These results demonstrate that the effects of blood resin on TTX-S
sodium current may contribute to loureirin B in blood resin. Perhaps the analgesic effect of blood resin is caused partly
by loureirin B directly interfering with the nociceptive transmission of primary sensory neurons. 相似文献
5.
LIU Xiangming CHEN Su YIN Shijin & MEI Zhinan . Department of Biological & Medical Engineering South-Central University for Nationalities Wuhan China . College of Chemistry & Biological Technology South-Central University for Nationalities Wuhan China 《中国科学:生命科学英文版》2004,(4)
Copyright by Science in China Press 2004 Dragons blood resin is one of famous precious Traditional Chinese Medicine (TCM), which has been widely applied in clinical treatment of cardiovascular disease, cervical spondylosis, gynecological disease, etc., due to its actions of dissipating blood stasis, eas-ing pain, arresting bleeding, promoting tissue regen-eration and wound healing[1]. At present, the investi-gation on the pharmacological mechanism of blood resin is concentrated on promoting… 相似文献
6.
LIU Xiangming CHEN Su YIN Shijin MEI Zhinan 《中国科学:生命科学英文版》2004,47(4):340-348
Using whole-cell patch clamp technique on the membrane of freshly isolated dorsal root ganglion (DRG) neurons, the effects of dragon’s blood resin and its important component loureirin B on tetrodotoxin-sensitive (TTX-S) voltage-gated sodium currents were observed. The results show that both blood resin and loureirin B could suppress TTX-S voltage-gated sodium currents in a dose-dependent way. The peak current amplitudes and the steady-state activation and inactivation curves are also made to shift by 0.05% blood resin and 0.2 mmol/L loureirin B. These results demonstrate that the effects of blood resin on TTX-S sodium current may contribute to loureirin B in blood resin. Perhaps the analgesic effect of blood resin is caused partly by loureirin B directly interfering with the nociceptive transmission of primary sensory neurons. 相似文献
7.
M Horackova 《Canadian journal of physiology and pharmacology》1985,63(11):1404-1410
Preparations of frog atrial muscle were stimulated at 0.33 Hz under voltage clamp, and the resulting membrane currents and the twitch contractions (phasic and tonic components) were recorded in presence or absence of D600. It has been suggested earlier that the tonic contractions are regulated by an electrogenic Na+-Ca2+ exchange, while the phasic contractions are closely related to the calcium inward current (Isi). In this study we investigated the effect of D600 on (i) the tonic contractions elicited by long depolarizing pulses of high amplitude and (ii) the tonic contractions increased by veratrine and resulting in a positive inotropic effect (PIE). While 1 microM D600 reduced Isi and the corresponding phasic contractions to less than 30% of their initial values within 5 min, the inhibitory effect of D600 on tonic contractions developed more slowly or higher concentrations of D600 were needed to achieve similar levels of inhibition within the same time. Furthermore, applications of 5-50 microM D600 inhibited the veratrine-induced increase in INa and in tonic contractions, and both of these effects again fully developed within a few minutes of D600 being removed. The results demonstrate that D600 inhibits not only Isi and phasic contractions, but it also decreases the tonic contractions in frog heart. The effect on the tonic component is associated with inhibition of the tetrodotoxin-sensitive Na+ inward current, and the results are interpreted as an effect of D600 on the electrogenic Na+-Ca2+ exchange. These additional effects of D600 should be considered when using this drug as the "specific" calcium channel blocker. 相似文献
8.
Opioids are the most effective analgesics for the treatment of moderate to severe pain. However, chronic opioid treatment can cause both hyperalgesia and analgesic tolerance, which limit their clinical efficacy. In this study, we determined the role of pre- and postsynaptic NMDA receptors (NMDARs) in controlling increased glutamatergic input in the spinal cord induced by chronic systemic morphine administration. Whole-cell voltage clamp recordings of excitatory postsynaptic currents (EPSCs) were performed on dorsal horn neurons in rat spinal cord slices. Chronic morphine significantly increased the amplitude of monosynaptic EPSCs evoked from the dorsal root and the frequency of spontaneous EPSCs, and these changes were largely attenuated by blocking NMDARs and by inhibiting PKC, but not PKA. Also, blocking NR2A- or NR2B-containing NMDARs significantly reduced the frequency of spontaneous EPSCs and the amplitude of evoked EPSCs in morphine-treated rats. Strikingly, morphine treatment largely decreased the amplitude of evoked NMDAR-EPSCs and NMDAR currents of dorsal horn neurons elicited by puff NMDA application. The reduction in postsynaptic NMDAR currents caused by morphine was prevented by resiniferatoxin pretreatment to ablate TRPV1-expressing primary afferents. Furthermore, intrathecal injection of the NMDAR antagonist significantly attenuated the development of analgesic tolerance and the reduction in nociceptive thresholds induced by chronic morphine. Collectively, our findings indicate that chronic opioid treatment potentiates presynaptic, but impairs postsynaptic, NMDAR activity in the spinal cord. PKC-mediated increases in NMDAR activity at nociceptive primary afferent terminals in the spinal cord contribute critically to the development of opioid hyperalgesia and analgesic tolerance. 相似文献
9.
Mason P 《Current opinion in neurobiology》2012,22(4):640-645
Neurons in the medullary raphe are critical to opioid analgesia through descending projections to the dorsal horn. Work in anesthetized rats led to the postulate that nociceptive suppression results from tonic activation of nociceptive-inhibiting neurons and tonic inhibition of nociceptive-facilitating neurons. However, morphine does not cause tonic changes in raphe neuronal firing in unanesthetized rodents. Recent work suggests that a drop in activity of nociceptive-inhibiting neurons synchronizes nociceptive circuits and a burst of activity in nociceptive-facilitating neurons facilitates withdrawal magnitude. After morphine, the phasic responses of raphe cells are suppressed along with nociceptive withdrawals. The results suggest a new model of brainstem modulation of nociception in which the medullary raphe facilitates nociceptive reactions when noxious input occurs and may modulate other functions between injurious events. 相似文献
10.
Inhibition of sodium currents by local anesthetics in chloramine-T- treated squid axons. The role of channel activation 总被引:9,自引:1,他引:8
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G K Wang M S Brodwick D C Eaton G R Strichartz 《The Journal of general physiology》1987,89(4):645-667
In order to test the requirement of Na channel inactivation for the action of local anesthetics, we investigated the inhibitory effects of quaternary and tertiary amine anesthetics on normally inactivating and noninactivating Na currents in squid axons under voltage clamp. Either the enzymatic mixture pronase, or chloramine-T (CT), a noncleaving, oxidizing reagent, was used to abolish Na channel inactivation. We found that both the local anesthetics QX-314 and etidocaine, when perfused internally at 1 mM, elicited a "tonic" (resting) block of Na currents, a "time-dependent" block that increased during single depolarizations, and a "use-dependent" (phasic) block that accumulated as a result of repetitive depolarizations. All three effects occurred in both control and CT-treated axons. As in previous reports, little time-dependent or phasic block by QX-314 appeared in pronase-treated axons, although tonic block remained. Time-dependent block was greatest and fastest at large depolarizations (Em greater than +60 mV) for both the control and CT-treated axons. The recovery kinetics from phasic block were the same in control and CT-modified axons. The voltage dependence of the steady state phasic block in CT-treated axons differed from that in the controls; an 8-10% reduction of the maximum phasic block and a steepening and shift of the voltage dependence in the hyperpolarizing direction resulted from CT treatment. The results show that these anesthetics can bind rapidly to open Na channels in a voltage-dependent manner, with no requirement for fast inactivation. We propose that the rapid phasic blocking reactions in nerve are consequences primarily of channel activation, mediated by binding of anesthetics to open channels, and that the voltage dependence of phasic block arises directly from that of channel activation. 相似文献
11.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients' quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I(NaT)) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I(NaT) and a decrease of potassium currents, especially slowly inactivating potassium currents (I(AS)); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I(NaT) and total potassium current as well as I(AS) currents induced by STZ were normalized by GAS. This study provides a clear cellular basis for the peripheral analgesic action of gastrodin for the treatment of chronic pain, including PDN. 相似文献
12.
Kia A Ribeiro F Nelson R Gavrilovici C Ferguson SS Poulter MO 《Journal of neurochemistry》2011,116(6):1043-1056
We have previously shown that after kindling (a model of temporal lobe epilepsy), the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) was unable to augment GABA type A receptor (GABA(A))-mediated synaptic currents occurring on pyramidal cells of the piriform cortex. Phosphorylation of GABA(A) receptors has been shown previously to alter the activity of THDOC, so we tested the hypothesis that kindling induces changes in the phosphorylation of GABA(A) receptors and this accounts for the loss in efficacy. To assay whether GABA(A) receptors are more phosphorylated after kindling, we examined the phosphorylation state of the β3 subunit and found that it was increased. Incubation of brain slices with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) (100 nM) also increased phosphorylation in the same assay. In patch clamp, recordings from non-kindled rat brain slices PMA also reduced the activity of THDOC in a manner that was identical to what is observed after kindling. We also found that the tonic current was no longer augmented by THODC after kindling and PMA treatment. The protein kinase C (PKC) antagonist bisindolylmaleimide I blocked the effects PMA on the synaptic but not the tonic currents. However, the broad spectrum PKC antagonist staurosporine blocked the effects of PMA on the tonic currents, implying that different PKC isoforms phosphorylate GABA(A) receptors responsible for phasic and tonic currents. The phosphatase activator Li(+) palmitate restored the 'normal' activity of THDOC on synaptic currents in kindled brain slices but not the tonic currents. These data demonstrate that kindling enhances the phosphorylation state of GABA(A) receptors expressed in pyramidal neurons reducing THDOC efficacy. 相似文献
13.
Tonic and phasic block of neuronal sodium currents by 5-hydroxyhexano- 2'',6''-xylide, a neutral lidocaine homologue 总被引:2,自引:0,他引:2
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The effects of a neutral lidocaine homologue, 5-hydroxyhexano-2',6'-xylidide (5-HHX), on the kinetics and amplitude of sodium currents in voltage-clamped amphibian nerve fibers are described. 5-HHX produced two types of sodium current inhibition: (a) tonic block, in resting fibers (IC50 approximately 2 mM), and (b) phasic block, an additional, incremental inhibition, in repetitively depolarized fibers (frequency greater than 1 Hz). The kinetics of phasic block were characterized by a single-receptor, switched-affinity model, in which binding increases during a depolarizing pulse and decreases between pulses. In the presence of 4 mM 5-HHX, binding increased during pulses from -80 to 0 mV, with an apparent rate constant of 6.4 +/- 1.4 s-1. Binding decreased between pulses with an apparent rate constant of 1.1 +/- 0.3 s-1. There was little effect of extracellular pH on the kinetics of phasic block. These findings demonstrate that neither the presence of a terminal amine nor a net charge on a local anesthetic is required for phasic block of sodium channels. 相似文献
14.
目的:研究奥卡西平(Oxcarbazepine,OXC)对大鼠三叉神经节神经元钙电流的调控作用。方法:SD大鼠随机分为3组(n=8):生理盐水组(NS组),致炎剂组(IS组),OXC预防组。应用膜片钳技术,采用全细胞记录方式,观察OXC对偏头痛大鼠急性分离的三叉神经节的高电压激活钙电流(HVA-ICa)的调控作用。结果:OXC能够抑制钙电流,使钙电流的激活曲线向去极化方向移动,使钙电流的失活曲线向超级化方向移动。结论:OXC可能通过抑制钙离子进入细胞膜,来预防偏头痛的发作。同时OXC可能对外周神经系统及伤害感受的传入的兴奋性起到调控作用。 相似文献
15.
Menthol is a widely-used cooling and flavoring agent derived from mint leaves. In the peripheral nervous system, menthol regulates sensory transduction by activating TRPM8 channels residing specifically in primary sensory neurons. Although behavioral studies have implicated menthol actions in the brain, no direct central target of menthol has been identified. Here we show that menthol reduces the excitation of rat hippocampal neurons in culture and suppresses the epileptic activity induced by pentylenetetrazole injection and electrical kindling in vivo. We found menthol not only enhanced the currents induced by low concentrations of GABA but also directly activated GABA(A) receptor (GABA(A)R) in hippocampal neurons in culture. Furthermore, in the CA1 region of rat hippocampal slices, menthol enhanced tonic GABAergic inhibition although phasic GABAergic inhibition was unaffected. Finally, the structure-effect relationship of menthol indicated that hydroxyl plays a critical role in menthol enhancement of tonic GABA(A)R. Our results thus reveal a novel cellular mechanism that may underlie the ambivalent perception and psychophysical effects of menthol and underscore the importance of tonic inhibition by GABA(A)Rs in regulating neuronal activity. 相似文献
16.
Cerebellar granule cells (CGNs) are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs) mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-Itonic) is controversial. Earlier studies suggested that GoCs mediate a component of CGN-Itonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-Itonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-Itonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na+/K+-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23–30). Under these conditions, we reliably detected a GoC-dependent component of CGN-Itonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-Itonic. Inhibition of the Na+/K+-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na+/K+-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system. 相似文献
17.
Olfactory receptor neurons (ORNs) respond to odorants with characteristic patterns of action potentials that are relevant for odor coding. Prolonged odorant exposures revealed three populations of dissociated toad ORNs, which were mimicked by depolarizing currents: tonic (TN, displaying sustained firing, 49% of 102 cells), phasic (PN, exhibiting brief action potential trains, 36%) and intermediate neurons (IN, generating trains longer than PN, 15%). We studied the biophysical properties underlying the differences between TNs and PNs, the most extreme cases among ORNs. TNs and PNs possessed similar membrane capacitances (approximately 4 pF), but they differed in resting potential (-82 versus -64 mV), input resistance (4.2 versus 2.9 G(Omega)) and unspecific current, I(u) (TNs: 0 < I(u) 1 pA/pF). Firing behavior did not correlate with differences in voltage-gated conductances. We developed a mathematical model that accurately simulates tonic and phasic patterns. Whole cell recordings from rat ORNs in fragments (approximately 4 mm(2)) of olfactory epithelium showed that such a tissue normally contains tonic and phasic receptor neurons, suggesting that this feature is common across a wide range of vertebrates. Our findings show that the individual passive electrical properties can govern the firing patterns of ORNs. 相似文献
18.
We recorded spike activity of noradrenergic neurons of zone A5 (n = 89) in the brain of anesthetized rats under conditions of hypoxic stimulation (breathing with pure N2, 10 sec), thermonociceptive stimulation (tail-flick test), and reversible hypothermal blocking of the central respiratory
activity. Hypoxic stimulation of peripheral O2-sensitive chemoreceptors considerably increased the discharge frequency in all the examined neurons and induced tachypnea
and a hypotensive reaction. Sixty-nine (77.5%) neurons of the studied group were tested using nociceptive stimulation (thermal
stimulation of the tail); such stimulation resulted in a multifold increase in their discharge frequency. This was accompanied
by tachypnea and a hypertensive response. Thus, we first demonstrated the role of nociception in the control of activity of
noradrenergic neurons in zone A5 and the role of nociceptive afferent signals in the modulation of functions of the respiratory
and cardiovascular systems mediated by neurons of the above zone. Under conditions of blocking of the central respiratory
activity, we examined 36 (40.4%) neurons of zone A5 and first observed the effect of strong activation of a significant proportion
of these cells upon switching off of respiration. This fact shows that there is an activating “respiratory” drive on neurons
of zone A5 (probably, from the side of an expiratory neuronal population of the respiratory center) and allows us to hypothesize
on the genesis of “respiratory” modulation of these cells. The activity of 16 (18.0%) cells was recorded under conditions
of consecutive applications of the above stimuli; all the neurons were activated by the respective afferent influences. The
simultaneously induced effects of hypoxic and nociceptive stimulations on the activity of neurons of zone A5 were additive.
Thus, we first obtained proofs in favor of the multimodality of noradrenergic neurons of the above zone. This feature is a
significant factor providing integrative interaction between the respiratory and cardiovascular systems and the system of
nociception.
Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 305–313, July–August, 2006. 相似文献
19.
Marc J.C. Scanio Lei Shi Irene Drizin Robert J. Gregg Robert N. Atkinson James B. Thomas Matthew S. Johnson Mark L. Chapman Dong Liu Michael J. Krambis Yi Liu Char-Chang Shieh XuFeng Zhang Gricelda H. Simler Shailen Joshi Prisca Honore Kennan C. Marsh Alison Knox Stephen Werness Brett Antonio Michael E. Kort 《Bioorganic & medicinal chemistry》2010,18(22):7816-7825
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. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Nav1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Nav1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Nav1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration. 相似文献
20.
Voltage-gated sodium channels(VGSCs) are transmembrane proteins responsible for generation and conduction of action potentials in excitable cells.Physiological and pharmacological studies have demonstrated that VGSCs play a critical role in chronic pain associated with tissue or nerve injury.Many long-chain peptide toxins(60-76 amino acid residues) purified from the venom of Asian scorpion Buthus martensii Karsch(BmK) are investigated to be sodium channel-specific modulators.The α-like neurotoxins that can ... 相似文献