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Pain States (pain + states)
Kinds of Pain States Selected AbstractsEFNS guidelines on pharmacological treatment of neuropathic painEUROPEAN JOURNAL OF NEUROLOGY, Issue 11 2006N. Attal Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools. [source] Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiologyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2009Theodore J. Price Abstract The increased sensitivity of peripheral pain-sensing neurons, or nociceptors, is a major cause of the sensation of pain that follows injury. This plasticity is thought to contribute to the maintenance of chronic pain states. Although we have a broad knowledge of the factors that stimulate changes in nociceptor sensitivity, the cellular mechanisms that underlie this plasticity are still poorly understood; however, they are likely to involve changes in gene expression required for the phenotypic and functional changes seen in nociceptive neurons after injury. While the regulation of gene expression at the transcriptional level has been studied extensively, the regulation of protein synthesis, which is also a tightly controlled process, has only recently received more attention. Despite the established role of protein synthesis in the plasticity of neuronal cell bodies and dendrites, little attention has been paid to the role of translation control in mature undamaged axons. In this regard, several recent studies have demonstrated that the control of protein synthesis within the axonal compartment is crucial for the normal function and regulation of sensitivity of nociceptors. Pathways and proteins regulating this process, such as the mammalian target of rapamycin signaling cascade and the fragile X mental retardation protein, have recently been identified. We review here recent evidence for the regulation of protein synthesis within a nociceptor's axonal compartment and its contribution to this neuron's plasticity. We believe that an increased understanding of this process will lead to the identification of novel targets for the treatment of chronic pain. [source] The medullary dorsal reticular nucleus enhances the responsiveness of spinal nociceptive neurons to peripheral stimulation in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003Christophe Dugast Abstract Single-unit spinal recordings combined with application of glutamate into the medullary dorsal reticular nucleus were used to assess the action of this nucleus upon deep dorsal horn neurons in rats. Injection of high glutamate concentrations (10 and 100 mm) induced a dramatic and long-lasting increase of the responses of wide-dynamic range neurons to electrical stimulation of the sciatic nerve in the noxious range, without affecting ongoing discharges. Post-stimulus time histograms revealed that this increase concerned the post-discharge, but not A- or C-fibre-mediated responses, which remained unchanged independently of the stimulation frequency applied. The onset of the glutamate-induced response enhancement occurred with a concentration-dependent time delay and developed slowly until its maximum. These data indicate that the medullary dorsal reticular nucleus exerts a facilitating action upon deep dorsal horn wide-dynamic range neurons by enhancing their capacity to respond to peripheral stimulation through prolongation of their discharge. This action is accompanied by the strengthening of wind-up of deep dorsal horn wide-dynamic range neurons, hence providing a plausible substrate for chronic pain states. These results are in agreement with previous behavioural studies suggesting a pronociceptive role for the dorsal reticular nucleus [Almeida et al. (1996) Brain Res. Bull., 39, 7,15; Almeida et al. (1999) Eur. J. Neurosci., 11, 110,122], and support the involvement of a reverberating circuit, previously described in morphological studies [Almeida et al. (1993) Neuroscience, 55, 1093,1106; Almeida et al. (2000) Eur. J. Pain, 4, 373,387], which probably operates only at a certain threshold of activation. [source] Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTP,S binding in the dorsal horn of the spinal cord of noninflamed and inflamed ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2000L. J. Drew Abstract The analgesic potential of cannabinoid (CB) receptor agonists is of clinical interest. Improved understanding of the mechanisms of action of cannabinoids at sites involved in the modulation of acute and sustained inflammatory nociceptive transmission, such as the spinal cord, is essential. In vivo electrophysiology was used to compare the effect of the synthetic CB agonist, HU210, on acute transcutaneous electrical-evoked responses of dorsal horn neurons of noninflamed anaesthetized rats and anaesthetized rats with a peripheral carrageenin inflammation. CB receptor G-protein coupling in lumbar spinal cord sections of noninflamed and carrageenin-inflamed rats was studied with in vitro autoradiography of guanylyl 5,-[,-[35S]thio]triphosphate ([35S]GTP,S) binding. Spinal HU210 significantly inhibited the C-fibre-mediated late (300,800 ms) postdischarge response of dorsal horn neurons of noninflamed and carrageenin-inflamed rats; the CB1 receptor antagonist SR141716A blocked the effect of HU210. HU210 had limited effects on A-fibre-evoked dorsal horn neuronal responses of both groups of rats. HU210 significantly increased [35S]GTP,S binding in the dorsal horn of the spinal cord of both groups of rats compared with basal [35S]GTP,S binding; SR141716A blocked these effects. The predominant effect of spinal HU210, via CB1 receptor activation, was on the C-fibre driven postdischarge responses, a measure of neuronal hyperexcitability following repetitive C-fibre stimulation. Sustained, but not enhanced, antinociceptive effects of HU210 following carrageenin inflammation are reported; CB receptor G-protein coupling was not altered by inflammation. These results strengthen the body of evidence suggesting CB agonists may be an important novel analgesic approach for the treatment of sustained pain states. [source] Is There Hope for Chronic Pain and Headache?HEADACHE, Issue 8 2007Marcela Romero-Reyes DDS Currently the clinical needs for pain and headache management are not met. Despite the numerous and exciting recent advances in understanding the molecular and cellular mechanisms that originate pain, we cannot yet fully explain the mechanism underlying the biology of chronic pain. Pain is a natural mechanism preserving our species survival; however, when the protective quality is lost, physiologic changes to the peripheral and central nervous systems result in the formation of chronic pain states. Once we understand how this chronic pain state is created, either through genetic, environmental, therapeutic, or other triggers we may be able to enhance our species existence, limiting maladaptive pain and suffering. The future therapeutic targets will need to address the genetics, neurophysiologic changes of the neurons and brain as well as help control immune systems including the glia. The key to successful headache and pain therapy is research aimed at prevention and minimizing the plastic changes triggering chronic pain. [source] Pain relief by gabapentin and pregabalin via supraspinal mechanisms after peripheral nerve injuryJOURNAL OF NEUROSCIENCE RESEARCH, Issue 15 2008Mitsuo Tanabe Abstract The antihypersensitivity actions of gabapentin and pregabalin have been well characterized in a large number of studies, although the underlying mechanisms have yet to be defined. We have been focusing on the supraspinal structure as a possible site for their action and have demonstrated that intracerebroventricular (i.c.v.) administration of gabapentin and pregabalin indeed decreases thermal and mechanical hypersensitivity in a murine chronic pain model involving partial ligation of the sciatic nerve. This novel supraspinally mediated analgesic effect was markedly suppressed by either depletion of central noradrenaline (NA) or blockade of spinal ,2 -adrenergic receptors. Moreover, i.c.v. injection of gabapentin and pregabalin increased spinal NA turnover in mice only after peripheral nerve injury. In locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury, gabapentin reduced the ,-aminobutyric acid (GABA) type A receptor-mediated inhibitory postsynaptic currents (IPSCs). Glutamate-mediated excitatory synaptic transmission was hardly affected. Moreover, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Although gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired-pulse ratio, suggesting that gabapentin acts on the presynaptic GABAergic nerve terminals in the LC. Together, the data suggest that gabapentin presynaptically reduces GABAergic synaptic transmission, thereby removing the inhibitory influence on LC neurons only in neuropathic pain states, leading to activation of the descending noradrenergic system. © 2008 Wiley-Liss, Inc. [source] Voltage-Gated Sodium Channels: Therapeutic Targets for PainPAIN MEDICINE, Issue 7 2009Sulayman D. Dib-Hajj PhD ABSTRACT Objective., To provide an overview of the role of voltage-gated sodium channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these channels as therapeutic targets for treating chronic pain. Background., Neuropathic and inflammatory pain conditions are major medical needs worldwide with only partial or low efficacy treatment options currently available. An important role of voltage-gated sodium channels in many different pain states has been established in animal models and, empirically, in humans, where sodium channel blockers partially ameliorate pain. Animal studies have causally linked changes in sodium channel expression and modulation that alter channel gating properties or current density in nociceptor neurons to different pain states. Biophysical and pharmacological studies have identified the sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently, gain-of-function mutations in SCN9A, the gene which encodes Nav1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence of Nav1.8, which suggests a similar physiological interaction of these two channels in humans carrying the Nav1.7 pain mutation. Conclusions., These studies suggest that isoform-specific blockers of these channels or targeting of their modulators may provide novel approaches to treatment of pain. [source] Synergistic Interactions Between a KCNQ Channel Opener and an Opioid: Flupirtine and Morphine in Rat Pain Models Including Neuropathic PainPAIN MEDICINE, Issue 7 2007C Goodchild Purpose of the study:, Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ 2,3 potassium channel opener. These experiments were performed to see if this property could be useful in treating more severe pain states characterised by central sensitisation with the drug either given alone or in combination with morphine. Methods:, Experiments were performed in rats in an observer blinded fashion with vehicle controls. Non sedating doses of flupirtine, morphine and combinations containing both drugs were defined using the rotarod technique. Dose response relationships were determined for non sedating doses of both drugs given alone and together in combination in causing antinociception in three nociception paradigms: electrical pain; carrageenan paw inflammation; streptozotocin-induced diabetic neuropathy. Results:, Flupirtine and morphine when given alone caused slight to moderate antinociception in all three paradigms. Flupirtine also caused significant increases in morphine antinociception in all three models. In carrageenan paw inflammation complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model (see figure) morphine 3.2 mg/kg given alone caused significant antinociception but the size of that response was significantly less than that caused by a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg (p < 0.001; one way ANOVA). Conclusions:, Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with severe pain states involving central sensitization. [source] Targeted Pharmacotherapy of Evoked Phenomena in Neuropathic Pain: A Review of the Current EvidencePAIN MEDICINE, Issue 1 2007BSc(Med), Ron Granot MB BS ABSTRACT Objective., Evoked phenomena in clinical neuropathic pain are viewed as a window into the underlying pathophysiology. They are also potential therapeutic targets. This study sought evidence for the effect on such evoked phenomena of currently used agents. Design., We reviewed MEDLINE (1966,2006) and EMBASE (1980,2006) to locate all randomized, double-blind, placebo-controlled trials examining therapeutic responses of evoked neuropathic pain phenomena, including dynamic mechanical allodynia, pin prick hyperalgesia, and thermal allodynia. We also noted the methods of elicitation of these evoked pain phenomena. Results., We found 40 articles meeting our inclusion criteria. A wide variety of methods was used to evoke neuropathic pain phenomena. For dynamic mechanical allodynia, there is some evidence for the efficacy of ketamine, alfentanil, and morphine, but only when administered intravenously. For other agents and other evoked pain phenomena, there is insufficient evidence to draw firm conclusions. Conclusions., There is minimal evidence to guide clinicians in treating evoked pain phenomena in clinical neuropathic pain states. There is little clinical evidence to either support or refute theoretical arguments for efficacy of specific agents in evoked neuropathic pain phenomena. More and larger trials are needed to examine these phenomena. Consensus is required with respect to methods used to elicit these evoked phenomena. [source] The behavioral importance of dynamically activated descending inhibition from the nucleus reticularis gigantocellularis pars alpha. (University Hospital of Wales, Cardiff, United Kingdom) Pain 2001;92:53,62.PAIN PRACTICE, Issue 4 2001J. Azami This study demonstrates the effects of nucleus reticularis gigantocellularis pars alpha (GiA) on the behavioral response during application of standardized noxious stimuli. As this system is activated in response to noxious stimulation, it is possible that chronic pain states may also activate GiA. Therefore, this study investigated this possibility in animals following partial sciatic nerve ligation (an animal model of chronic pain). Male Wistar rats (280,310 g) were anesthetized with halothane (0.5% to 2% in O2). Guide cannulae for microinjections were stereotaxically placed above GiA. In one group of animals the sciatic nerve was partially litigated. Animals were allowed to recover for 4,6 days. The responses of each animal during the formalin test and the tail flick test were recorded on different days. Microinjections (0.5 ,l) of either ,-aminobutyric acid (GABA, 200 mM), D-L homocysteic acid (DLH, 25 mM), or 0.9% saline (as control) into GiA were preformed during these tests in a randomized, blind manner. In animals without sciatic nerve ligation, microinjection of GABA to GiA did not significantly affect the animal's response during the tail flick test. However, microinjection of DLH significantly increased the latency of tail flick from 6.2 ± 0.8 to 8.4 ± 0.5 seconds for up to 15 minutes. Microinjection of GABA to GiA increased the behavioral response to formalin between 10 and 20 minutes postinjection, while microinjection of DLH reduced this response at all time points except 10 minutes postinjection (n = 8, p < 0.05, Mann-Whitney U -test). In animals with sciatic nerve ligation, microinjections (0.5 ,l) of either GABA (200 mM), or saline (as control) into GiA contralateral to the partial sciatic ligation were performed during these tests in a randomized, blind manner. Partial sciatic ligation significantly reduced the behavioral response to contralaterally applied formalin from 15 minutes postinjection onwards, compared to controls without sciatic nerve ligation. Microinjection of GABA GiA significantly increased the behavioral response to formalin from 20 to 50 minutes postinjection. The inactivation of GiA only causes behavioral effects in nociceptive tests of a long enough duration to activate the system (ie, the formalin test but not the tail flick test). Chemical activation of the system affects both tests. Conclude that these data strongly support the concept of an important analgesic system that is activated in response to noxious stimulation, and subsequently acts to reduce behavioral responses to noxious stimuli. Comment by Leland Lou, M.D. This is a rat study that looked at the presence of inhibitory spinal multireceptive cells modifying and decreasing the behavioural response to noxious stimuli. While no direction was given as to the source of noxious stimuli inhibition in chronic pain, great effort was made to report a possible differential response of the C-fiber pain system versus the large sensory fibers. After review it seems that the authors believed that the nucleus reticularis gigantocellularis pars alpha maybe a central processor of the inhibitory response. It is still too early to assess the clinical impact of this study. [source] Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010Jerzy Karczewski BACKGROUND AND PURPOSE Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid-sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons. EXPERIMENTAL APPROACH To examine the contribution of ASIC3 to the development and maintenance of muscle pain and inflammatory pain, we studied the in vivo efficacy of a selective ASIC3 inhibitor, APETx2, in rats. KEY RESULTS Administration of APETx2 into the gastrocnemius muscle prior to the administration of low pH saline prevented the development of mechanical hypersensitivity, whereas APETx2 administration following low-pH saline was ineffective in reversing hypersensitivity. The prevention of mechanical hypersensitivity produced by acid administration was observed whether APETx2 was applied via i.m. or i.t. routes. In the complete Freund's adjuvant (CFA) inflammatory pain model, local administration of APETx2 resulted in a potent and complete reversal of established mechanical hypersensitivity, whereas i.t. application of APETx2 was ineffective. CONCLUSIONS AND IMPLICATIONS ASIC3 contributed to the development of mechanical hypersensitivity in the acid-induced muscle pain model, whereas ASIC3 contributed to the maintenance of mechanical hypersensitivity in the CFA inflammatory pain model. The contribution of ASIC3 to established hypersensitivity associated with inflammation suggests that this channel may be an effective analgesic target for inflammatory pain states. [source] | |||||||||||||||||||||||||