Meta-analysis of transcutaneous electrical nerve stimulation for relief of spinal pain.

We conducted a systematic review and meta-analysis analysing the existing data on transcutaneous electrical nerve stimulation (TENS) or interferential current (IFC) for chronic low back pain (CLBP) and/or neck pain (CNP) taking into account intensity and timing of stimulation, examining pain, function and disability. Seven electronic databases were searched for TENS or IFC treatment in non-specific CLBP or CNP. Four reviewers independently selected randomized controlled trials (RCTs) of TENS or IFC intervention in adult individuals with non-specific CLBP or CNP. Primary outcomes were for self-reported pain intensity and back-specific disability. Two reviewers performed quality assessment, and two reviewers extracted data using a standardized form. Nine RCTs were selected (eight CLBP; one CNP), and seven studies with complete data sets were included for meta-analysis (655 participants). For CLBP, meta-analysis shows TENS/IFC intervention, independent of time of assessment, was significantly different from placebo/control (p < 0.02). TENS/IFC intervention was better than placebo/control, during therapy (p = 0.02), but not immediately after therapy (p = 0.08), or 1-3 months after therapy (p = 0.99). Analysis for adequate stimulation parameters was not significantly different, and there was no effect on disability. This systematic review provides inconclusive evidence of TENS benefits in low back pain patients because the quality of the studies was low, and adequate parameters and timing of assessment were not uniformly used or reported. Without additional high-quality clinical trials using sufficient sample sizes and adequate parameters and outcome assessments, the outcomes of this review are likely to remain unchanged. SIGNIFICANCE: These data highlight the need for additional high-quality RCTs to examine the effects of TENS in CLBP. Trials should consider intensity of stimulation, timing of outcome assessment and assessment of pain, disability and function.

Effects of the carrier frequency of interferential current on pain modulation and central hypersensitivity in people with chronic nonspecific low back pain: A randomized placebo-controlled trial.

BACKGROUND: Interferential current (IFC) is commonly used for pain relief, but the effects of carrier frequency of the current and its action on pain mechanisms remain unclear. This randomized placebo-controlled trial tested the effects of IFC in people with chronic nonspecific low back pain. METHODS: One hundred and fifty participants were randomly allocated into three groups: 1 kHz, 4 kHz and placebo. The primary outcomes were pain intensity at rest in the first session (immediate effect of the IFC), after 12 sessions, 4 months after randomization (follow-up) and during movement (first and last session). The secondary outcomes were disability, global perceived effect, functional performance, discomfort caused by the IFC, use of analgesics and physiological measures of pain. RESULTS: Only during the first session, there was a significant decrease in pain intensity in the active groups. However, there were no differences in the improvement of pain at rest or during movement in the active groups compared to the placebo group in the remaining sessions. The frequency use of analgesics was significantly decreased in the active groups. For pain physiology measures, there was a significant increase in pressure pain thresholds in both active groups compared to the placebo group and a reduction in the temporal summation in the 1 kHz group compared to the other groups. CONCLUSIONS: These results suggest that although the IFC has changed some physiological mechanisms of pain and showed decrease frequency use of pain medication, there was no change in the primary aim, pain intensity. WHAT DOES THIS STUDY ADD?: The interferential current (IFC) presented advantages in the physiological measures of pain and showed decrease frequency use of pain medication. Future studies should investigate analgesic intake with IFC treatment.

Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans.

BACKGROUND: Research in animal models suggests that transcutaneous electrical nerve stimulation (TENS) and conditioned pain modulation (CPM) produce analgesia via two different supraspinal pathways. No known studies have examined whether TENS and CPM applied simultaneously in human subjects will enhance the analgesic effect of either treatment alone. The purpose of the current study was to investigate whether the simultaneous application of TENS and CPM will enhance the analgesic effect of that produced by either treatment alone. METHODS: Sixty healthy adults were randomly allocated into two groups: (1) CPM plus active TENS; (2) CPM plus placebo TENS. Pain threshold for heat (HPT) and pressure (PPT) were recorded from subject's left forearm at baseline, during CPM, during active or placebo TENS, and during CPM plus active or placebo TENS. CPM was induced by placing the subjects' contralateral arm in a hot water bath (46.5 °C) for 2 min. TENS (100 µs, 100 Hz) was applied to the forearm for 20 min at a strong but comfortable intensity. RESULTS: Active TENS alone increased PPT (but not HPT) more than placebo TENS alone (p = 0.011). Combining CPM and active TENS did not significantly increase PPT (p = 0.232) or HPT (p = 0.423) beyond CPM plus placebo TENS. There was a significant positive association between PPT during CPM and during active TENS (r(2) = 0.46; p = 0.003). CONCLUSIONS: TENS application increases PPT; however, combining CPM and TENS does not increase the CPM's hypoalgesic response. CPM effect on PPT is associated with the effects of TENS on PPT.

Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats.

Transcutaneous electric nerve stimulation (TENS) is widely used for the treatment of pain. TENS produces an opioid-mediated antinociception that utilizes the rostroventromedial medulla (RVM). Similarly, antinociception evoked from the periaqueductal grey (PAG) is opioid-mediated and includes a relay in the RVM. Therefore, we investigated whether the ventrolateral or dorsolateral PAG mediates antinociception produced by TENS in rats. Paw and knee joint mechanical withdrawal thresholds were assessed before and after knee joint inflammation (3% kaolin/carrageenan), and after TENS stimulation (active or sham). Cobalt chloride (CoCl(2); 5 mM) or vehicle was microinjected into the ventrolateral periaqueductal grey (vlPAG) or dorsolateral periaqueductal grey (dlPAG) prior to treatment with TENS. Either high (100 Hz) or low (4 Hz) frequency TENS was then applied to the inflamed knee for 20 min. Active TENS significantly increased withdrawal thresholds of the paw and knee joint in the group microinjected with vehicle when compared to thresholds prior to TENS (P<0.001) or to sham TENS (P<0.001). The increases in withdrawal thresholds normally observed after TENS were prevented by microinjection of CoCl(2) into the vlPAG, but not the dlPAG prior to TENS and were significantly lower than controls treated with TENS (P<0.001). In a separate group of animals, microinjection of CoCl(2) into the vlPAG temporarily reversed the decreased mechanical withdrawal threshold suggesting a role for the vlPAG in the facilitation of joint pain. No significant difference was observed for dlPAG. We hypothesize that the effects of TENS are mediated through the vlPAG that sends projections through the RVM to the spinal cord to produce an opioid-mediated analgesia.

Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice.

The acid sensing ion channel 3 (ASIC3) is critical for the development of secondary hyperalgesia as measured by mechanical stimulation of the paw following muscle insult. We designed experiments to test whether ASIC3 was necessary for the development of both primary and secondary mechanical hyperalgesia that develops after joint inflammation. We used ASIC3 -/- mice and examined the primary (response to tweezers) and secondary hyperalgesia (von-Frey filaments) that develops after joint inflammation comparing to ASIC3 +/+ mice. We also examined the localization of ASIC3 to the knee joint afferents innervating the synovium using immunohistochemical techniques before and after joint inflammation. We show that secondary mechanical hyperalgesia does not develop in ASIC3 -/- mice. However, the primary mechanical hyperalgesia of the inflamed knee joint still develops in ASIC3 -/- mice and is similar to ASIC3 +/+ mice. In knee joint synovium from ASIC3 +/+ mice without joint inflammation, ASIC3 was not localized to joint afferents that were stained with an antibody to protein gene product (PGP) 9.5 or calcitonin gene-related peptide (CGRP). ASIC3 was found, however, in synoviocytes of the knee joint of uninflamed mice. In ASIC3 +/+ mice with joint inflammation, ASIC3 co-localized with PGP 9.5 or CGRP in joint afferents innervating the synovium. We conclude that the decreased pH that occurs after inflammation would activate ASIC3 on primary afferent fibers innervating the knee joint, increasing the input to the spinal cord resulting in central sensitization manifested behaviorally as secondary hyperalgesia of the paw.

Low frequencies, but not high frequencies of bi-polar spinal cord stimulation reduce cutaneous and muscle hyperalgesia induced by nerve injury.

Spinal cord stimulation (SCS) is an established treatment for neuropathic pain. However, SCS is not effective for all the patients and the mechanisms underlying the reduction in pain by SCS are not clearly understood. To elucidate the mechanisms of pain relief by SCS, we utilized the spared nerve injury model. Sprague-Dawley rats were anesthetized, the tibial and common peroneal nerves were tightly ligated, and an epidural SCS lead implanted in the upper lumbar spinal cord. SCS was delivered daily at one of 4 different frequencies (4Hz, 60Hz, 100Hz, and 250Hz) at approximately 85% of motor threshold 2 weeks after nerve injury for 4 days. Mechanical withdrawal threshold of the paw and compression withdrawal threshold of the hamstring muscles were measured before and after SCS on each day. All rats showed a decrease in withdrawal threshold of the paw and the muscle 2 weeks after nerve injury. Treatment with either 4Hz or 60Hz SCS significantly reversed the decreased withdrawal threshold of the paw and muscle. The effect was cumulative with a greater reversal by the fourth treatment when compared to the first treatment. Treatment with 100Hz, 250Hz or sham SCS had no significant effect on the decreased withdrawal threshold of the paw or muscle that normally occurs after nerve injury. In conclusion, SCS at 4Hz and 60Hz was more effective in reducing hyperalgesia than higher frequencies of SCS (100Hz and 250Hz); and repeated treatments result in a cumulative reduction in hyperalgesia.

Release of GABA and activation of GABA(A) in the spinal cord mediates the effects of TENS in rats.

Transcutaneous electrical nerve stimulation (TENS) is a commonly utilized non-pharmacological, non-invasive treatment for pain. GABA is a neurotransmitter in the dorsal horn of the spinal cord that mediates analgesia locally, and also through activation of supraspinal sites. TENS reduces hyperalgesia through activation of receptor-mediated pathways at the level of the spinal cord, and supraspinally. The current study tested the hypothesis that either high or low frequency TENS applied to the inflamed knee joint increases GABA in the spinal cord dorsal horn and activates GABA receptors spinally. We utilized microdialysis to sample the extracellular fluid before, during and after TENS and analyzed GABA in dialysates with high performance liquid chromatography. We analyzed the extracellular GABA concentrations in animals with and without knee joint inflammation induced by intra-articular injection of kaolin and carrageenan. We further tested if spinal blockade of GABA receptors prevents the antihyperalgesia produced by TENS in rats with joint inflammation. We show that high frequency TENS increases extracellular GABA concentrations in the spinal cord in animals with and without joint inflammation. The increases in GABA do not occur in response to low frequency TENS, and there are no increases in glycine in response to low or high frequency TENS. However, the reduction in primary hyperalgesia by both high and low frequency TENS is prevented by spinal blockade of GABA(A) receptors with bicuculline. Thus, high frequency TENS increases release of GABA in the deep dorsal horn of the spinal cord, and both high and low frequency TENS reduce primary hyperalgesia by activation of GABA(A) receptors spinally.

Excitatory amino acid concentrations increase in the spinal cord dorsal horn after repeated intramuscular injection of acidic saline.

Chronic muscle pain is common and often difficult to treat. In this study, we further characterize a model of chronic muscle pain induced by repeated intramuscular injection of acidic saline. Two injections of acid into muscle separated by 5 days result in secondary mechanical hyperalgesia that lasts for up to 4 weeks. Blockade of spinal NMDA receptors prior to the second injection intramuscular acid injection delays the onset of hyperalgesia, where as the maintenance phase of hyperalgesia, evaluated 1 week after the second intramuscular injection, is dependent on activation of spinal AMPA/kainate and NMDA receptors. In order to determine if behavioral hyperalgesia and glutamate receptor involvement are associated with increased concentrations of excitatory amino acids (EAA), we utilized microdialysis to evaluate extracellular glutamate and aspartate concentrations in the spinal dorsal horn during the first and second intramuscular acid injections, and 1 week after the development of mechanical hyperalgesia. The second intramuscular injection evoked a calcium-dependent increase in both spinal glutamate and aspartate concentrations. Glutamate concentrations within the dorsal horn were also increased 1 week after the second acid injection. Our data suggest increased release of spinal EAAs in the dorsal horn contributes to the development and maintenance of hyperalgesia.

High-frequency, but not low-frequency, transcutaneous electrical nerve stimulation reduces aspartate and glutamate release in the spinal cord dorsal horn.

Transcutaneous electrical nerve stimulation (TENS) is a commonly utilized non-pharmacological treatment for pain. Studies show that low- and high-frequency TENS utilize opioid, serotonin and/or muscarinic receptors in the spinal cord to reduce hyperalgesia induced by joint inflammation in rats. As there is an increase in glutamate and aspartate levels in the spinal cord after joint inflammation, and opioids reduce glutamate and aspartate release, we hypothesized that TENS reduces release of glutamate and aspartate in animals with joint inflammation by activation of opioid receptors. Using microdialysis and HPLC with fluorescence detection, we examined the release pattern of glutamate and aspartate in the dorsal horn in response to either low-frequency (4 Hz) or high-frequency (100 Hz) TENS. We examined the effects of TENS on glutamate and aspartate release in animals with and without joint inflammation. High-frequency, but not low-frequency, TENS significantly reduced spinal glutamate and aspartate in animals with joint inflammation compared with levels in those without joint inflammation. The reduced release of glutamate and aspartate by high-frequency TENS was prevented by spinal blockade of delta-opioid receptors with naltrindole. Thus, we conclude that high-frequency TENS activates delta-opioid receptors consequently reducing the increased release of glutamate and aspartate in the spinal cord.

Spinal muscarinic receptors are activated during low or high frequency TENS-induced antihyperalgesia in rats.

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological modality used clinically to relieve pain. Central involvement of serotonin and endogenous opioids are implicated in TENS-induced analgesia. Activation of spinal cholinergic receptors is antinociceptive and these receptors interact with opioid and serotonin receptors. In the current study, the possible involvement of spinal cholinergic receptors in TENS analgesia was investigated in rats. Hyperalgesia was induced by inflaming one knee joint with 3% kaolin-carrageenan and assessed by measuring paw withdrawal latency (PWL) to heat before and 4 h after injection. The non-selective nicotinic antagonist mecamylamine (50 microg), non-selective muscarinic antagonist atropine (30 microg) or one of the muscarinic subtype antagonists: pirenzepine (M1, 10 microg), methoctramine (M2, 10 microg), 4-DAMP (M3, 10 microg), or saline was administered intrathecally just prior to TENS treatment. Low or high frequency TENS was then applied to the inflamed knee and PWL was determined again. Atropine, pirenzepine and 4-DAMP significantly attenuated the antihyperalgesic effects of low and high frequency TENS while mecamylamine and methoctramine had no effects, compared to saline control. The results show that TENS-induced antihyperalgesia is mediated partially by activation of spinal muscarinic receptors but not spinal nicotinic receptors. Further, the results also indicate that spinal M1 and M3 muscarinic receptor subtypes mediate the muscarinic component of TENS antihyperalgesia.

Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS).

Although transcutaneous electrical nerve stimulation (TENS) is used extensively in inflammatory joint conditions such as arthritis, the underlying mechanisms are unclear. This study aims to demonstrate an opiate-mediated activation of descending inhibitory pathways from the rostral ventral medulla (RVM) in the antihyperalgesia produced by low- (4 Hz) or high-frequency (100 Hz) TENS. Paw withdrawal latency to radiant heat, as an index of secondary hyperalgesia, was recorded before and after knee joint inflammation (induced by intra-articular injection of 3% kaolin and carrageenan) and after TENS/no TENS coadministered with naloxone (20 microg/1 microl), naltrindole (5 microg/1 microl), or vehicle (1 microl) microinjected into the RVM. The selectivity of naloxone and naltrindole doses was tested against the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) (20 ng, 1 microl) and the delta2-opioid receptor agonist deltorphin (5 microg, 1 microl) in the RVM. Naloxone microinjection into the RVM blocks the antihyperalgesia produced by low frequency (p < 0.001), but not that produced by high-frequency TENS (p > 0.05). In contrast, naltrindole injection into the RVM blocks the antihyperalgesia produced by high-frequency (p < 0.05), but not low-frequency (p > 0.05) TENS. The analgesia produced by DAMGO and deltorphin is selectively blocked by naloxone (p < 0.05) and naltrindole (p < 0.05), respectively. Thus, the dose of naloxone and naltrindole used in the current study blocks mu- and delta-opioid receptors, respectively. Hence, low-frequency and high-frequency TENS produces antihyperalgesia by activation of mu- and delta-opioid receptors, respectively, in the RVM.

Nonpharmacological treatments for musculoskeletal pain.

BACKGROUND: Several types of physical therapy are used in the management of painful musculoskeletal disorders. These treatment modalities can be broadly categorized as electrotherapy modalities (e.g., transcutaneous electrical nerve stimulation), acupuncture, thermal modalities (e.g., moist heat, ultrasound), manual therapies (e.g., manipulation or massage), or exercise. Within each of these broad categories significant variations in treatment parameters are possible. OBJECTIVE: To consider the evidence base for each of these main categories of physical therapy in the management of musculoskeletal pain. METHOD: To consider the available evidence related to clinical effectiveness and then to review evidence from basic science studies evaluating potentially therapeutic effects of the various therapies. RESULTS: There seems to be evidence from basic science research to suggest that many of the therapies could have potentially therapeutic effects. However, there appears to be limited high-quality evidence from randomized clinical trials to support the therapeutic effectiveness of several of the therapies. CONCLUSIONS: There is some preliminary evidence to support the use of manual therapies, exercise, and acupuncture in the management of some categories of musculoskeletal pain. Limitations of the existing research base are discussed and recommendations for areas of future research are provided.

Reduction in inflammation-induced sensitization of dorsal horn neurons by transcutaneous electrical nerve stimulation in anesthetized rats.

Transcutaneous electrical nerve stimulation (TENS) is utilized to treat a variety of painful conditions. Inflamed animals present with an increased response to noxious stimuli, i.e., hyperalgesia, at the site of injury (primary hyperalgesia) and outside the site of injury (secondary hyperalgesia). Further, following acute inflammation, dorsal horn neurons show an increased responsiveness to peripherally applied stimuli, which has been termed sensitization. Previous studies demonstrate a reduction in dorsal horn neuron activity following TENS treatment in normal animals and a reduction in primary and secondary hyperalgesia in acutely inflamed animals. The purpose of this study was to examine the effects of TENS on dorsal horn neurons sensitized by acute inflammation. Extracellular recordings from wide dynamic range (WDR), high threshold (HT) and low threshold (LT) dorsal horn neurons in anesthetized rats were assessed for spontaneous activity, responses to innocuous and noxious mechanical stimulation and receptive field size. Responses were measured before and 3 h after induction of inflammation, and immediately and 1 h after application of either high (100 Hz) or low (4 Hz) frequency TENS (motor intensity, pulse duration = 100 microseconds). TENS was applied to the inflamed paw to encompass the receptive field of the neuron for 20 min. WDR and HT dorsal horn neurons sensitized to mechanical stimulation after induction of inflammation. Application of either high or low frequency TENS to the inflamed paw reduced both innocuous and noxious evoked responses of WDR and HT dorsal horn neurons immediately and 1 h after treatment with TENS. Comparison of responses after TENS with baseline responses showed that the evoked responses in the majority of WDR and HT cells returned to or fell below baseline responses. TENS had no effect on responses of LT neurons. In summary, central neuron sensitization is reduced by TENS and may underlie the reduction in hyperalgesia observed after treatment with TENS.

Low frequency TENS is less effective than high frequency TENS at reducing inflammation-induced hyperalgesia in morphine-tolerant rats.

Both transcutaneous electrical nerve stimulation (TENS) and morphine are commonly used for relief of pain. Extensive research has been done on the effectiveness of each of these two methods for pain relief when given independently. However, very little literature exists examining the effectiveness of their combined use. Systemically administered morphine activates mu opioid receptors and when administered for prolonged periods results in analgesic tolerance. Low (4 Hz) and high (100 Hz) frequency TENS activate mu- and delta-opioid receptors, respectively, It is thus possible that TENS would be less effective in morphine-tolerant subjects. The current study investigated the effectiveness of high- and low-frequency TENS in the reversal of hyperalgesia in inflamed rats that were morphine-tolerant. Morphine tolerance was induced by subcutaneous implantation of morphine pellets over 10 days. Knee joint inflammation was induced by injection of kaolin and carrageenan into the knee joint cavity. Secondary heat hyperalgesia was tested by measuring the paw withdrawal latency to radiant heat (1) before pellet implantation (either morphine or placebo), (2) after pellet implantation and before inflammation, (3) after inflammation and (4) after TENS. Both high (100 Hz) and low (4 Hz) frequency TENS caused nearly 100% inhibition of secondary hyperalgesia in animals receiving placebo pellets. In contrast, the hyperalgesia in morphine-tolerant animals with knee joint inflammation was unaffected by low frequency TENS but fully reversed by high frequency TENS. These results suggest that patients who are tolerant to morphine may respond better to high frequency TENS than to low frequency TENS.

Effect of varying frequency, intensity, and pulse duration of transcutaneous electrical nerve stimulation on primary hyperalgesia in inflamed rats.

OBJECTIVES: To examine the effect of varying frequency, intensity, and pulse duration of transcutaneous electrical nerve stimulation (TENS) on primary hyperalgesia (increased response to a noxious stimuli) to heat and mechanical stimuli induced by carrageenan paw inflammation in rats. DESIGN: Inflammation was induced by injection of 3% carrageenan into the hindpaw. Two frequencies (high, 100 Hz; low, 4 Hz), 2 intensities (high, motor; low, sensory), and 2 pulse durations (100 microsec, 250 microsec) were applied for 20 minutes to the inflamed paw. The paw withdrawal latency (PWL) to radiant heat, threshold to mechanical stimuli, and spontaneous pain-related behaviors were measured before and 4 hours after induction of inflammation, after TENS, and at 8, 12, and 24 hours after inflammation. A 3-factor (frequency, intensity, pulse duration) repeated-measures (time) design was used to analyze the changes in PWL. Mechanical threshold and spontaneous pain-related behaviors were compared for frequency, intensity, and pulse duration with a Kruskal-Wallis analysis of variance. RESULTS: For changes in PWL to heat, there was an effect for time (p = .0001) and frequency (p =.0001), but not for intensity (p = .45) or pulse duration (p = .21). For changes in mechanical threshold, there was also an effect for frequency (p = .007), but not for intensity (p = .055) or pulse duration (p = .058), after treatment with TENS. High-frequency TENS significantly reduced the primary hyperalgesia to heat and mechanical stimuli when compared with controls receiving no TENS or treatment with low-frequency TENS. High-frequency motor TENS also reduced spontaneous pain-related behaviors for 1 day after treatment. CONCLUSION: High-frequency TENS reduces primary hyperalgesia to heat and mechanical stimuli for up to 1 day after treatment. In contrast, low-frequency TENS is ineffective in reducing primary hyperalgesia. Varying intensity or pulse duration had no effect on the degree of antihyperalgesia produced by high-frequency TENS.

Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats.

Transcutaneous electrical nerve stimulation (TENS) is commonly used for relief of pain. The literature on the clinical application of TENS is extensive. However, surprisingly few reports have addressed the neurophysiological basis for the actions of TENS. The gate control theory of pain is typically used to explain the actions of high-frequency TENS, whereas, low-frequency TENS is typically explained by release of endogenous opioids. The current study investigated the role of mu, delta, and kappa opioid receptors in antihyperalgesia produced by low- and high-frequency TENS by using an animal model of inflammation. Antagonists to mu (naloxone), delta (naltrinodole), or kappa (nor-binaltorphimine) opioid receptors were delivered to the spinal cord by microdialysis. Joint inflammation was induced by injection of kaolin and carrageenan into the knee-joint cavity. Withdrawal latency to heat was assessed before inflammation, during inflammation, after drug (or artificial cerebral spinal fluid as a control) administration, and after drug (or artificial cerebral spinal fluid) administration + TENS. Either high- (100 Hz) or low- frequency (4 Hz) TENS produced approximately 100% inhibition of hyperalgesia. Low doses of naloxone, selective for mu opioid receptors, blocked the antihyperalgesia produced by low-frequency TENS. High doses of naloxone, which also block delta and kappa opioid receptors, prevented the antihyperalgesia produced by high-frequency TENS. Spinal blockade of delta opioid receptors dose-dependently prevented the antihyperalgesia produced by high-frequency TENS. In contrast, blockade of kappa opioid receptors had no effect on the antihyperalgesia produced by either low- or high-frequency TENS. Thus, low-frequency TENS produces antihyperalgesia through mu opioid receptors and high-frequency TENS produces antihyperalgesia through delta opioid receptors in the spinal cord.

Treatment with either high or low frequency TENS reduces the secondary hyperalgesia observed after injection of kaolin and carrageenan into the knee joint.

For years, physical therapists have been utilizing a variety of modalities, including transcutaneous electrical nerve stimulation (TENS), in an attempt to manage pain associated with inflammation. However, the data on clinical effectiveness is conflicting and the neurophysiological mechanism of action is not known. The purpose of this study was to investigate the effects of high and low frequency TENS on the secondary hyperalgesia that occurs after joint inflammation. Secondary hyperalgesia is thought to reflect changes in central neurons and is thus a measure of activity of central neurons. This study utilized the kaolin and carrageenan model of knee joint inflammation and measured the effects of TENS treatment on paw withdrawal latency to radiant heat (secondary hyperalgesia), spontaneous pain behaviors and joint circumference. Either high (100 Hz) or low (4 Hz) frequency TENS was applied to the knee joint for 20 min after the development of hyperalgesia. Both high and low frequency TENS resulted in a reversal of the hyperalgesia immediately following treatment. The effects of high frequency TENS lasted through at least 24 h while those of low frequency TENS lasted through 12 h. There was no effect of TENS on spontaneous pain behaviors or joint swelling when compared to controls. Thus, TENS appears to be more effective in reducing referred pain (or secondary hyperalgesia) without affecting guarding or splinting of the affected limb. Thus, clinically, the choice to use TENS may depend on patient symptoms; specifically TENS should be effective in reducing referred or radiating pain.

Blockade of calcium channels can prevent the onset of secondary hyperalgesia and allodynia induced by intradermal injection of capsaicin in rats.

Intradermal capsaicin injection in humans results in primary hyperalgesia to heat and mechanical stimuli applied near the injection site, as well as secondary mechanical hyperalgesia (increased pain from noxious stimuli) and mechanical allodynia (pain from innocuous stimuli) in an area surrounding the site of primary hyperalgesia. This study in rats tested the hypothesis that the secondary hyperalgesia and allodynia observed following intradermal injection of capsaicin was dependent upon activation of voltage sensitive calcium channels in the spinal cord. Responses to application of von Frey filaments of 10 mN and 90 mN bending forces were tested in all rats before and after injection of capsaicin into the plantar surface of a hindpaw. Animals were pretreated with L-type (nifedipine), N-type (omega-conotoxin GVIA) or P-type (omega-agatoxin IVA) calcium channels blockers through a microdialysis fiber implanted in the spinal dorsal horn prior to the injection of capsaicin. None of the calcium channel blockers had any affect on normal sensory or motor responses. However, all three blockers dose dependently prevented the development of secondary mechanical hyperalgesia and allodynia. The threshold to mechanical stimulation with von Frey filaments was also increased significantly in animals treated with these calcium channel blockers when compared to articial cerebrospinal fluid control animals. These data suggest that calcium channels are important for the development of mechanical hyperalgesia and allodynia that occurs following capsaicin injection.

Inhibitors of G-proteins and protein kinases reduce the sensitization to mechanical stimulation and the desensitization to heat of spinothalamic tract neurons induced by intradermal injection of capsaicin in the primate.

Intradermal injection of capsaicin results in sensitization of spinothalamic tract cells to brushing and pressure applied to the cutaneous receptive field in anesthetized monkeys. A significant increase in background activity also occurs immediately after capsaicin injection that lasts for at least 2 h. A 40-50% decrease in the response to noxious heat stimuli is also observed following capsaicin injection. This study investigated the spinal role of second messengers by extracellularly recording from spinothalamic tract cells and delivering inhibitors of second messenger pathways to the spinal cord by microdialysis. Blockade of protein kinases with the general protein kinase inhibitor, H7 (5.0 mM, n = 6), reduced the sensitization of the cells to brush and pressure. Blockade of protein kinase C with NPC15437 (10.0 mM, n = 10) reduced the increased background activity and the increased responses to brush. Blockade of protein kinase A with H89 (0.01 mM, n = 9) was most effective. H89 reduced the background activity, the increased responses to brush and press, and reversed the decreased response to noxious heat stimuli. Blockade of G-proteins with the general G-protein inhibitor, GDP-beta-S (1.0 mM, n = 9), reduced the background activity and the responses to brush and pressure without affecting the decreased response to heat. Thus, multiple intracellular messengers appear to be involved in the processing of central sensitization induced by activation of C-fibers following intradermal injection of capsaicin.

Differential effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on spinal release of amino acids after development of acute arthritis in rats.

Following induction of acute knee joint arthritis in rats, an increase in the release of amino acids in the spinal dorsal horn occurs in two phases: (1) at the time of injection for all amino acids tested; and (2) a late prolonged phase for aspartate (Asp) and glutamate (Glu) (3.5-8 h). In the present study, the increased late phase release of Glu was reversed by posttreatment of the spinal cord with the N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, but not with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Asp late phase release in arthritic animals was unaffected by posttreatment of the spinal cord with either AP7 or CNQX. Arthritic animals became hyperalgesic to radiant heat stimuli by 4 h and this hyperalgesia was reversed by both CNQX and AP7. During the paw withdrawal latency (PWL) test for heat hyperalgesia, there was an increase in the glycine (Gly) and serine (Ser) concentrations in the dorsal horn. This increase in Gly and Ser was blocked by both CNQX and AP7. Indications of inflammation in arthritic animals posttreated with AP7, including increased joint circumference and temperature, were similar to animals that did not receive antagonists. Arthritic animals posttreated with CNQX, however, showed a reduction in the degree of joint swelling. Thus, both non-NMDA and NMDA receptors appear to play a role in the processing of the information evoked by stimuli in the periphery. The arthritis-induced release of Gly and Ser during the PWL test for heat hyperalgesia appears to be dependent on activation of both non-NMDA and NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)