Transmission Of Noxious Stimuli Research Articles

Erythromelalgia Mutation Q875E Stabilizes the Activated State of Sodium Channel Nav1.7

The human voltage-gated sodium channel Nav1.7 plays a crucial role in transmission of noxious stimuli. The inherited pain disorder erythromelalgia (IEM) has been linked to Nav1.7 gain-of-function mutations. Here we show that the IEM-associated Q875E mutation located on the pore module of Nav1.7 produces a large hyperpolarizing shift (-18 mV) in the voltage dependence of activation. Three-dimensional homology modeling indicates that the side chains of Gln-875 and the gating charge Arg-214 of the domain I voltage sensor are spatially close in the activated conformation of the channel. We verified this proximity by using an engineered disulfide bridge approach. The Q875E mutation introduces a negative charge that may modify the local electrical field experienced by the voltage sensor and, upon activation, interact directly via a salt bridge with the Arg-214 gating charge residue. Together these processes could promote transition to, and stabilization of, the domain I voltage sensor in the activated conformation and thus produce the observed gain of function. In support of this hypothesis, an increase in the extracellular concentration of Ca(2+) or Mg(2+) reverted the voltage dependence of activation of the IEM mutant to near WT values, suggesting a cation-mediated electrostatic screening of the proposed interaction between Q875E and Arg-214.

A rat knockout model implicates TRPC4 in visceral pain sensation

Acute and chronic pain resulting from injury, surgery, or disease afflicts >100million Americans each year, having a severe impact on mood, mental health, and quality of life. The lack of structural and functional information for most ion channels, many of which play key roles in the detection and transmission of noxious stimuli, means that there remain unidentified therapeutic targets for pain management. This study focuses on the transient receptor potential canonical subfamily 4 (TRPC4) ion channel, which is involved in the tissue-specific and stimulus-dependent regulation of intracellular Ca2+ signaling. Rats with a transposon-mediated TRPC4-knockout mutation displayed tolerance to visceral pain induced by colonic mustard oil (MO) exposure, but not somatic or neuropathic pain stimuli. Moreover, wild-type rats treated with a selective TRPC4 antagonist (ML-204) prior to MO exposure mimicked the behavioral responses observed in TRPC4-knockout rats. Significantly, ML-204 inhibited visceral pain-related behavior in a dose-dependent manner without noticeable adverse effects. These data provide evidence that TRPC4 is required for detection and/or transmission of colonic MO visceral pain sensation. In the future, inhibitors of TRPC4 signaling may provide a highly promising path for the development of first-in-class therapeutics for this visceral pain, which may have fewer side effects and less addictive potential than opioid derivatives.

Acid-Sensing Ion Channels (ASICs) in pain

The discovery of new drug targets represents a real opportunity for developing fresh strategies against pain. Ion channels are interesting targets because they are directly involved in the detection and the transmission of noxious stimuli by sensory fibres of the peripheral nervous system and by neurons of the spinal cord. Acid-Sensing Ion Channels (ASICs) have emerged as important players in the pain pathway. They are neuronal, voltage-independent depolarizing sodium channels activated by extracellular protons. The ASIC family comprises several subunits that need to associate into homo- or hetero-trimers to form a functional channel. The ASIC1 and ASIC3 isoforms are particularly important in sensory neurons, whereas ASIC1a, alone or in association with ASIC2, is essential in the central nervous system. The potent analgesic effects associated with their inhibition in animals (which can be comparable to those of morphine) and data suggesting a role in human pain illustrate the therapeutic potential of these channels.

Alternative splicing in the C‐terminus of CaV2.2 controls expression and gating of N‐type calcium channels

N-type Ca(V)2.2 calcium channels localize to presynaptic nerve terminals of nociceptors where they control neurotransmitter release. Nociceptive neurons express a unique set of ion channels and receptors important for optimizing their role in transmission of noxious stimuli. Included among these is a structurally and functionally distinct N-type calcium channel splice isoform, Ca(V)2.2e[37a], expressed in a subset of nociceptors and with limited expression in other parts of the nervous system. Ca(V)2.2[e37a] arises from the mutually exclusive replacement of e37a for e37b in the C-terminus of Ca(V)2.2 mRNA. N-type current densities in nociceptors that express a combination of Ca(V)2.2e[37a] and Ca(V)2.2e[37b] mRNAs are significantly larger compared to cells that express only Ca(V)2.2e[37b]. Here we show that e37a supports increased expression of functional N-type channels and an increase in channel open time as compared to Ca(V)2.2 channels that contain e37b. To understand how e37a affects N-type currents we compared macroscopic and single-channel ionic currents as well as gating currents in tsA201 cells expressing Ca(V)2.2e[37a] and Ca(V)2.2e[37b]. When activated, Ca(V)2.2e[37a] channels remain open for longer and are expressed at higher density than Ca(V)2.2e[37b] channels. These unique features of the Ca(V)2.2e[37a] isoform combine to augment substantially the amount of calcium that enters cells in response to action potentials. Our studies of the e37a/e37b splice site reveal a multifunctional domain in the C-terminus of Ca(V)2.2 that regulates the overall activity of N-type calcium channels in nociceptors.

Reboxetine, placebo and paroxetine comparison in patients with major depressive disorder: A double-blind, placebo- and comparator-controlled study

The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development—eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development.

Cyclic AMP regulates substance P expression in developing and mature spinal sensory neurons.

The tachykinin, substance P, has long been associated with transmission of noxious stimuli. However, relatively little is known about signal transduction pathways subserving peptidergic regulation in sensory neurons. To investigate whether cyclic AMP (cAMP) could be a potential second messenger subserving substance P expression, dorsal root ganglion neurons were grown in culture in the presence of agents that increase content of cAMP. In developing neurons, forskolin increased substance P content and survival almost threefold. Anti-nerve growth factor (NGF) blocked the effect of NGF but not forskolin, suggesting that increased cAMP acts directly and not via increased secretion of NGF from Schwann cells and fibroblasts. In adult neurons, which do not require supplemental trophic factors for survival, NGF and forskolin had similar effects on substance P levels. Neither agent had any effect on somatostatin content of either developing or mature sensory neurons. 8-bromo cAMP and isobutyl methylxanthine duplicated the action of forskolin. Further, all three agents increased expression of preprotachykinin mRNA. Forskolin appeared to increase both total and neuron-specific expression of message as well as the number of neurons expressing mRNA. Our results suggest that cAMP directly regulates substance P content in sensory neurons from adult and neonatal rats.

The neuronal response to pain

A great deal of information has been obtained about the normal physiology of pain transmission. This information has been utilised in the development of techniques, such as transcutaneous electrical nerve stimulation and dorsal column stimulation, to relieve pain symptoms. This review will discuss the role of both the peripheral and the central nervous systems in the transmission of noxious stimuli. It will also discuss the neuronal response to pain involving spinal, thalamic and cortical neurons, as well as the descending inhibitory control systems. The response of peripheral and central neurons in pain models such as arthritis and peripheral neuropathy is altered. There is an increase in the neuronal response to peripherally applied stimuli following tissue or nerve injury that involves spinal, thalamic and cortical neurons. Increased activation of the endogenous descending inhibitory systems also occurs in response to injury. Both the peripheral and central nervous systems are ‘plastic', they can be modified and show considerable adaptation to injury. The severity of some diseases and injuries does not allow the body to control associated pain, resulting in chronic pain. Models of chronic pain syndromes are beginning to provide insight into the pathophysiology of injury and disease. Research in this area will hopefully provide better treatments for the chronic pain patient.

Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress?

Since the first comprehensive description of the symptoms of FMS by Yunus et al (1981), numerous investigations have confirmed that FMS is a clinical entity. However, the aetiology of the syndrome is still not fully elucidated. It seems, however, logical to place the origin of the disorder in the muscle. Muscle pain, especially at the muscle-tendon junctions, fatigue and stiffness are the first symptoms. A malfunction of energy metabolism has been detected in part of the muscle fibres. However, it has to be considered that the muscle is not an isolated entity. Its activity is controlled by segmentally arranged motor units of the ventral horn of the spinal cord in response to proprioceptive afferent signals arising in the muscle spindles or in other sensory elements including nociceptors. Together with supraspinal descending inputs, the spinal motor neurone pool is the common final pathway for segmental and suprasegmental inputs, making the motor system extremely powerful for adaptive adjustments but also vulnerable if deficits occur in either of these input levels. A second, recently discovered abnormality seen in FMS is a lowered serotonin level in peripheral and most likely also central structures. The underlying mechanism seems to be defective absorption of the precursor amino acid tryptophan from the gut. Serotonin is involved centrally in the regulation of the sleep pattern, and at the spinal level it acts as a 'gain setter' of motoneurone excitability and suppresses signal transmission of noxious stimuli in dorsal horn neurones. Either of these two disturbances, muscle energy depletion or serotonin deficiency, could by itself evoke many of the symptoms of FMS, and their combined appearance will perpetuate the disease. Depressed levels of somatomedin C, caused by a deficit of stage 4 sleep-dependent release of GH, might represent an additional factor in preventing proper development or repair of myoskeletal structures. Malabsorption of certain amino acids, possibly due to a genetic disorder of gut transport mechanisms, may constitute an additional deleterious factor. The abnormalities found in the HPA and HPT axis may be seen as an attempt of the organism to restore homeostasis. The stimulus eliciting this counter-regulatory reaction may be pain or other afferent signals which normally do not reach the central nervous system. It is doubtful whether the unspecific activation of the HPA axis in a non-inflammatory disease is beneficial.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferents to the zona incerta in the rat: a combined retrograde and anterograde study.

In a first set of experiments, the retrograde transport of horseradish peroxidase (HRP) was utilized to investigate the afferent projections to the zona incerta (ZI) in the hooded rat. HRP was introduced in its crystalline form into various sectors of the ZI of seven subjects. The largest contingent of afferents arises from the following centers: the cingulate and somatosensory cortices, central amygdaloid nucleus, ventromedial hypothalamic nucleus, posterior thalamic nucleus, anterior pretectal nucleus, peripeduncular area, deep and intermediate layers of the superior colliculus, dorsal and ventral parabrachial nuclei, principal and interpolar trigeminal subnuclei, and cuneate nucleus. Other centers less systematically or more sparsely labeled were the lateral hypothalamic area, ventrobasal complex, lateral geniculate nucleus pars ventralis, medial geniculate nucleus, interstitial nucleus of Cajal, Darkschewitsch nucleus, perirubral fields, cuneiform, tegmental pedunculopontine, and deep mesencephalic reticular nuclei, pontine reticular nucleus pars oralis, lateral and interpositus cerebellar nuclei, and gracile nucleus. In a second set of experiments, an anterograde tracer (WGA-HRP) was injected in several centers projecting to the ZI in order to localize their terminal fields within this structure. It has been thus possible to distinguish a ventral zone (ventral sector of pars caudalis and pars ventralis) in which the somesthetic (somatosensory cortex, trigeminal complex, and dorsal column nuclei (DCN), collicular, and cerebellar projections terminate, from a dorsal zone (pars dorsalis) to which a limbic input (cingulate cortex and ventromedial hypothalamic nucleus) is directed. In most cases, the labeled terminal fields consisted of well-delimited, narrow bands disposed obliquely, parallel to the cerebral peduncle or the internal capsule. The contingent of somatosensory afferents is relatively large and there is a high degree of overlapping between the different somatosensory terminal fields within the ventral ZI. This suggests a participation of this structure in the treatment of somesthetic information and/or in the transmission of noxious stimuli.

For Acute Pain?

Alleviation of pain is important to the recovery of postoperative patients. The pain they suffer has no useful physiologic purpose. It only results in anxiety, suffering, and pathophysiologic complications if mismanaged. The traditional strategy for managing postoperative pain has been to administer narcotic and non-narcotic analgesics. But not only do narcotics cause a physiological depression that can retard recovery, they are not always effective. From 5 to 20 percent of patients treated with narcotics do not obtain effective relief, and 80 percent report the relief does not last long(1,2). Since 1974, transcutaneous electrical nerve stimulation (TENS) has been promoted as a noninvasive alternative to traditional narcotic analgesia for the management of acute postoperative pain(3-8). In addition to being noninvasive, TENS appears to be simple, safe, and without systemic side effects. How the electrical stimulation of nerves is able to produce analgesia is not certain. One hypothesis, based on the control theory of pain, postulates that electrical stimulation of large peripheral nerve fibers closes the gate so that painful stimuli cannot get to the spinal cord cells(9). Another suggests that the nerve stimulation triggers the release of endorphins that attach to opiate receptors on the excitatory neuron, so that the transmission of noxious stimuli is inhibited(10). Although a number of studies show TENS to be effective in man-

Dextran-Local Anesthetic Interactions

A number of clinical investigators have found that low molecular weight (LMW) dextran prolongs the action of local anesthetics on peripheral nerve. Other reports indicate no significant change in duration with these combinations. We performed a series of experiments to determine if LMW dextran interacted with lidocaine or bupivacaine so that the duration of block would be enhanced. Millipore filtration, equilibrium dialysis, and membrane ultrafiltration were performed with 14C-lidocaine in the presence and absence of LMW dextran to determine whether any binding existed between LMW dextran and lidocaine which might prolong a block by retarding the egress of the local anesthetic. In all cases, the lidocaine crossed the 8,000 to 10,000 molecular weight barriers as quickly with LMW dextran as without it. To confirm these findings in vivo, 14C-lidocaine, with and without 5% LMW dextran, was infused into the infraorbital nerve of rats. Thirty minutes after the block was established, the animals were killed and the nerves removed and sectioned. The amount of lidocaine still present was the same whether or not LMW dextran was added. If the amount of lidocaine present is not altered, then its effect must be enhanced if a prolonged block is to be produced. Increased refractory period would increase the effect of a given concentration of lidocaine or other local anesthetic on the transmission of noxious stimuli. LMW dextran 5% did not increase the block of 0.25 mM lidocaine on frog sciatic in vitro at frequencies from 1 to 100 Hz. Direct assessment of the effect of LMW dextran was made by injecting 1 mg of bupivacaine or 2 mg of lidocaine with or without 5% LMW dextran into the rat maxillary nerve and assessing the duration of nerve block. In both cases, block duration was the same whether or not dextran was added. These data suggest that LMW dextran does not affect the kinetics of lidocaine nor does it enhance the action of lidocaine or bupivacaine in other ways, and thus these data support the findings of those who see no prolongation of action when LMW dextran is added to lidocaine or bupivacaine.