The journal of pain : official journal of the American Pain Society
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Injury to the nerve can produce changes in dorsal horn function and pain. This facilitated processing may be mediated in part by voltage-sensitive calcium channels. Activation of these channels increases intracellular calcium, thereby mediating transmitter release and activating cascades serving to alter membrane excitability and initiate protein transcription. Molecular techniques reveal the complexity and multiplicity of these channels. At the spinal level, blocking of several of these calcium channels, notably those of the N type, can prominently alter pain behavior. These effects are consistent with the high levels of expression on primary afferents and dorsal horn neurons of these channels. More recently, agents binding to auxiliary subunits such as the alpha2delta of these calcium channels diminish excitability of the membrane without completely blocking channel function. Drugs that bind to this site, highly expressed in the superficial dorsal horn, will diminish neuropathic pain states. Continuing developments in our understanding of these channel functions promises to advance the control of aberrant spinal functions initiated by nerve injury. ⋯ Pharmacologic studies showing the role of spinal voltage-sensitive calcium channels in neuropathic pain models provide evidence suggesting their applicability in human pain states.
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A number of experimental studies in animals have suggested that voltage-gated sodium channels may play a crucial role in neuropathic pain. However, it is still difficult to translate the pathophysiological mechanisms identified in animal studies to the clinic and several questions regarding the role of sodium channels in neuropathic pain must therefore be addressed primarily in the clinical setting. Despite providing indirect information, pharmacologic challenge using sodium channel blockers, such as some antiepileptics, local anesthetics and derivatives, is the best way to investigate the role of sodium channels in the various clinical symptoms of neuropathies (eg, spontaneous pain, mechanical or thermal allodynia, and hyperalgesia). Randomized controlled trials have demonstrated the efficacy of these compounds for various neuropathic pain conditions. Recent psychophysical studies in which symptoms and signs are more accurately assessed indicate that these compounds act as antihyperalgesic agents rather than as simple analgesics. They also show that the sensitivity to these drugs is not affected by the aetiology of pain and the peripheral or central location of the nerve lesion. These data emphasize the role of peripheral and central sodium channels in neuropathic pain. Studies using more selective sodium channel blockers are required to gain further insight into the role of the various subtypes of sodium channel in these pain conditions. ⋯ Pharmacological challenge using sodium channel blockers is the best way to translate basic research on sodium channels in human neuropathic pain. To date, the role of sodium channels in neuropathic pain symptoms/signs is mostly documented for mechanical static and dynamic allodynia, and either peripheral or central sodium channels may be involved.
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Pain draws on attentional resources, thereby disturbing the pursuit of ongoing activities. Several studies have made use of the primary task paradigm to study the disruptive function of pain on attention. In this paradigm, participants perform an attentionally demanding task, while they are occasionally distracted by mild electrical stimulation. Deterioration in task performance (in terms of speed and accuracy) is then taken as an index of attentional interference. One major finding with this paradigm was that pain catastrophizing enhances attentional interference. The current study aimed to replicate this finding and to explore the possible influence of anxiety sensitivity and injury/illness sensitivity on attentional interference. Healthy volunteers (n = 48) performed an auditory discrimination task and were thereby occasionally distracted by low electrocutaneous stimulations. The performance on the discrimination task was subsequently related to participants' scores on the Pain Catastrophizing Scale, the Anxiety Sensitivity Index, and the Injury/illness Sensitivity Index. We were unable to demonstrate an association of either injury/illness sensitivity or anxiety sensitivity with attentional interference. Results did, however, confirm the finding that pain catastrophizing enhances attentional interference. ⋯ The present study showed that pain disrupts ongoing activities. This effect is enlarged in those with high levels of pain catastrophizing and is related to the threatening nature of pain stimuli. The role of anxiety sensitivity and injury/illness sensitivity seems to differ from the role of catastrophizing and needs further research.
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Devices designed for mechanical pain threshold studies are often difficult to implement. The purpose of this study was to investigate a simple tool based on calibrated forceps to induce quantifiable mechanical stimulation in the rat on a linear scale. The most suitable protocol was tested by determining the effects of 3 repetitive measurements on both hind paws, respectively, during long-term (9 days), mid-term (1 day), and short-term (2 hours). Only threshold increase related to weight gain over long-term was observed, suggesting that moderate rat training can be used. The capacity of the device to reveal hyperalgesia was tested in a model of carrageenan-induced inflammation in the hind paw. The hyperalgesia was maximal 6 hours after carrageenan injection and progressively decreased. Similar, although more variable, responses were observed with von Frey filaments. Morphine-induced analgesia resulted in a dose-dependent increase of paw threshold. Tolerance to morphine administrated on a once daily schedule (10 mg/kg) during 5 days was revealed by a significant decrease in analgesia by day 3. Taken together, these results demonstrated accuracy of this device for easy, fast, and reproducible measure of mechanical pain threshold on rat limbs. Moreover, it allows the performance of rat testing with minimal constraint, which reduces data variability. ⋯ The calibrated forceps is an easy to use device well-suited to rapidly test mechanical pain threshold with accuracy. It is well-designed for preclinical behavioral screening of noxious or analgesic properties of molecules.
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Chronic neuropathic pain due to injury or dysfunction of the nervous system remains a formidable treatment challenge in spite of a growing range of medication choices. We review current clinical research supporting the use of ion channel modulators for neuropathic pain states. New modes of local drug delivery, novel Ca2+ channel targets, and increased choices for drugs with activity at Na+channels are transforming this longstanding therapeutic strategy. Clinical decision making is increasingly informed by a more nuanced understanding of the role of voltage-gated Na+channels (VGSCs) and Ca2+ channels (VGCCs) in the pathophysiology of nerve injury. Although holding great promise for the future, mechanism-based approaches to treatment will require greater understanding of the analgesic mechanisms of drug action and of the relationships between pathophysiologic mechanisms and clinical presentation. ⋯ Treatment options for neuropathic pain targeting ion channels have grown rapidly in the past decade. An evolving body of clinical research supports the widespread use of this longstanding therapeutic strategy. Improved efficacy of ion channel modulators hinges upon further elucidation of the relationship between signs and symptoms of pain and underlying pathophysiology.