Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats

Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100 Hz) or low frequency (4 Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner.     

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.     

An investigation of the development of analgesic tolerance to TENS in humans

Transcutaneous electrical nerve stimulation (TENS) is a noninvasive modality used to control pain. Animal models show that repeated TENS application produces analgesic tolerance and cross-tolerance at spinal opioid receptors. The aim of the present investigation was to examine whether repeated application of TENS produces analgesic tolerance in humans. One hundred healthy subjects were randomly assigned to 1 of 4 groups: control, placebo, low-frequency (4 Hz) or high-frequency (100 Hz) TENS. TENS was applied daily for 5 days to the nondominant upper limb; pressure-pain threshold (PPT) measurements were recorded before and after TENS. Temporal summation to mechanical stimulation was recorded on days 1 and 5, before and after TENS. Diffuse noxious inhibitory control (DNIC) was tested on day 5 using the cold pressor test and PPT measurements. There was an initial increase in PPTs in both low- and high-frequency TENS groups when compared with placebo or control groups. However, by day 5 this TENS-induced increase in PPT did not occur, and there was no difference between active TENS and placebo or control groups. High-frequency TENS decreased temporal summation on day 1 when compared with day 5. DNIC increased the PPT similarly in all groups. These data suggest that repeated daily application of TENS results in a decrease in its hypoalgesic effect by the fifth day and that the tolerance-like effect to repeated TENS results from tolerance at centrally located opioid receptors. The lack of change in DNIC response suggests that TENS and DNIC utilize separate pathways to produce analgesia.     

Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats.

Repeated daily application of transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the antihyperalgesia produced by TENS. Since N-methyl-D-aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists, we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minutes daily at high-frequency (100 Hz), low-frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg to 0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation and before and after TENS treatment for 4 days. On day 1, TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4, TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle, demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4, demonstrating that tolerance did not develop. Vehicle-treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. PERSPECTIVE: Observed tolerance to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan.     

Central post-stroke pain--the effect of high and low frequency TENS

The effect of high (conventional) and low frequency (acupuncture-like) transcutaneous electrical nerve stimulation (Hi-, Lo-TENS) was tested in 15 patients with central post-stroke pain. During the initial 16 day trial of stimulation ipsilateral and contralateral to the pain, 4 patients obtained pain relief. Three of them benefitted from ipsilateral Hi- and Lo-TENS. Two patients also obtained pain relief with contralateral stimulation. Three patients continued to use TENS ipsilaterally with good effect at follow-up 23-30 months after the initial trial. In one-third of the patients, TENS temporarily increased the pain.     

Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats

DeSantana JM, Santana-Filho VJ, Sluka KA. Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats.

Objective

To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance.

Design

Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%-2%).

Setting

Laboratory.

Animals

Adult male Sprague-Dawley rats (N=36).

Intervention

Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100μs pulse duration.

Main Outcome Measures

Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS.

Results

The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds.

Conclusions

These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop.     

调制中频电流与低频电流的镇痛作用观察

目的 观察调制中叔电流与低频电流的镇痛作用和探讨电脑程序编制规律,对比观察了两组不同的中频电流和ＴＥＮＳ对人体痛阈的作用,并比较了受试者对这些电流的舒适度的评价。方法 两组中频电流中,一组为常规的参数多变的电流,电流处方号为１１;另一组为自编的参数变化减少的电流,处方号为２５。健康成人１０名,每天随机接受１种电流刺激和作对照处理。结果 作用后即刻,２５与处方的电流与ＴＥＮＳ及１１号处方电流的镇痛效果对比,差异均有非常显著性（均Ｐ〈０．０１）,１１号处方的电流与ＴＥＮＳ对比,差异无显著性（Ｐ〉０．０５）;作用后１５ｍｉｎ,三种电流之间仅２５号处方的电流与ＴＥＮＳ对比,差异有显著性（Ｐ〈０．０５）。电流舒适度,１１号处方的电流与２５号处方的电流与ＴＥＮＳ对比,差异有非常显著性（Ｐ〈０．０１）。结论 ２５号处方的电流     

Effects of TENS frequency, intensity and stimulation site parameter manipulation on pressure pain thresholds in healthy human subjects

This study evaluated the effects of varying frequency, intensity and stimulation site, of transcutaneous electrical nerve stimulation (TENS) in an experimental model of pain. In a double-blind design 240 volunteers were randomised to one of six experimental TENS groups, a sham TENS or control (n=30 per group; gender balanced). Two TENS frequencies (110 or 4 Hz) and two intensities (strong but comfortable or highest tolerable) at a fixed pulse duration (200 micros) were applied at three sites relative to the measurement site (segmentally, extrasegmentally or a combination of these), for 30 min. Pressure pain thresholds (PPT) were measured using a pressure algometer, in the first dorsal interosseous muscle, every 10 min, during stimulation and for a further 30 min. The high frequency, high intensity segmental, and combined stimulation groups, showed rapid onset and significant hypoalgesic effects. This effect was sustained for 20 min post-stimulation in the high frequency segmental group. All other TENS intervention groups showed hypoalgesic responses similar to the sham TENS group, and none of these groups reached a clinically significant hypoalgesic level. CONCLUSIONS: The role of TENS frequency, intensity and site are pivotal to achieving optimal hypoalgesic effects, during and after stimulation. Clinical applications of these parameter combinations require further investigations.     

Inhibition of the human flexion reflex by low intensity, high frequency transcutaneous electrical nerve stimulation (TENS) has a gradual onset and offset

The present study examines the inhibitory effect of segmentally applied TENS on the nociceptive component of the flexion reflex elicited in various lower limb muscles, in an attempt to gain some insight into the underlying mechanism. The flexion reflex from 11 normal subjects was recorded electromyographically from the biceps femoris (BF), the tibialis anterior (TA), and in 2 subjects, the hip flexor (HF), in the manner described in a previous paper [9]. Amplitude and area values of the flexion reflex of each muscle were computerized prior to, during, and 50 min after the application of placebo or low intensity TENS at 100 Hz, for 30 min to the low back, at levels of segmental innervation (L4-S1) similar to those of the muscles under study. In the majority of subjects, we found that: Low intensity TENS caused a significant inhibition of the flexion reflex in proximal limb flexors. Thus, the BF measured 64% and 52%, and the HF 45% and 51%, of their respective mean control amplitude and area values at the time of maximum inhibition during TENS. Moreover, less reduction of the mean values of the flexion reflex was observed in the TA, a distal limb (ankle) flexor. It is noteworthy that in both the BF and HF, the time to peak maximum inhibitory effect took 30 and 20 min respectively after the onset of TENS, and the flexion reflex often did not return to control values even at 40-50 min after TENS. In contrast, placebo TENS application resulted in no significant change of the flexion reflex in all the muscles examined. These findings showed that prolonged stimulation of large diameter fibers by conventional TENS application to the lumbosacral level, exerts a progressive and long latency inhibitory influence on a number of lower limb flexor motoneurons. In keeping with functional demand, this effect was found to be more prominent on the proximal than distal limb muscles. Furthermore, a gradual onset and offset of this inhibitory action is consistent with the results of some investigators demonstrating the possible involvement of endogenous opioids.     

A comparison of the analgesic efficacy of medium-frequency alternating current and TENS

Objective

To compare the analgesic efficacy of burst-modulated medium-frequency alternating current (BMAC) and transcutaneous electrical nerve stimulation (TENS) using an experimental cold pain model.

Design

Within-group crossover study.

Setting

A university research laboratory.

Participants

Twenty healthy subjects.

Interventions

BMAC (4-kHz AC applied in 4-millisecond bursts at 50 Hz) and TENS (125-microsecond phase duration applied at a frequency of 50 Hz) administered to each participant on separate occasions.

Main outcome measure

Time to cold pain threshold.

Results

The mean time to cold pain threshold with the BMAC intervention was no different than with TENS. Statistical analysis showed that both interventions elevated the cold pain threshold significantly [BMAC: increase = 15.2 seconds, 97.5% confidence interval (CI) 3.1 to 27.2, P = 0.01; TENS: increase = 15.4 seconds, 97.5%CI 2.5 to 28.4, P = 0.02], and the difference between interventions was not simply insignificant but the intervention effects were ‘significantly the same’ (mean difference = 0.3 seconds, 95%CI −15.3 to 15.9, P = 0.97).

Conclusions

BMAC is as effective as TENS in increasing cold pain thresholds in healthy subjects. Since BMAC has been shown to be more comfortable than TENS in previous studies and is likely to be better accepted and tolerated by patients, clinical investigation is warranted.     

Modulation of heat pain perception by high frequency transcutaneous electrical nerve stimulation (TENS).

Although many studies have indicated that high frequency nonpainful transcutaneous electrical nerve stimulation (TENS) reduces clinical pain, controlled studies of the modulation of experimental pain by TENS have produced conflicting results. This study evaluated the effect of high frequency nonpainful TENS on heat pain perception using a model that we have previously shown to be sensitive to other nonpharmacological analgesic treatments. We found that TENS significantly reduced subjects' ratings of painful and near painful heat stimuli (43-51 degrees C) (p = 0.01) and increased the pain threshold from 46.7 to 47.9 degrees C (p = 0.002). Placebo stimulation had no effect on the subjects' ratings or on their pain thresholds. Furthermore, TENS did not alter subjects' ratings of visual stimuli, indicating that the analgesic effect was not due to a nonspecific distraction. These data suggest that TENS alters the perception of experimentally produced natural pain stimuli. The TENS related modulation also appears to be comparable to that produced by other nonpharmacological analgesic manipulations such as counterirritation and changes in attention.     

Catastrophizing delays the analgesic effect of distraction

Behavioral analgesic techniques such as distraction reduce pain in both clinical and experimental settings. Individuals differ in the magnitude of distraction-induced analgesia, and additional study is needed to identify the factors that influence the pain relieving effects of distraction. Catastrophizing, a set of negative emotional and cognitive processes, is widely recognized to be associated with increased reports of pain. We sought to evaluate the relationship between catastrophizing and distraction analgesia. Healthy participants completed three sessions in a randomized order. In one session (Pain Alone), pain was induced by topical application of a 10% capsaicin cream and simultaneous administration of a tonic heat stimulus. In another session (Pain + Distraction), identical capsaicin + heat application procedures were followed, but subjects played video games that required a high level of attention. During both sessions, verbal ratings of pain were obtained and participants rated their degree of catastrophizing. During the other session (Distraction Alone) subjects played the video games in the absence of any pain stimulus. Pain was rated significantly lower during the distraction session compared to the “Pain Alone” session. In addition, high catastrophizers rated pain significantly higher regardless of whether the subjects were distracted. Catastrophizing did not influence the overall degree of distraction analgesia; however, early in the session high catastrophizers had little distraction analgesia, though later in the session low and high catastrophizers rated pain similarly. These results suggest that both distraction and catastrophizing have substantial effects on experimental pain in normal subjects and these variables interact as a function of time.     

Ultrasonic treatment of tumors-III high intensity,low frequency exposures

Hamster fibrosarcomas were exposed to 1.06 MHz ultrasound at intensities of 90 W/cm² in a pulse mode (0.1 sec on, 0.9 sec off) to avoid excessive heating. Tumor temperatures ranged from 19 to 30°C during these exposures. The treatment had no apparent effect on the rate of growth of the primary tumor or on the rate of metastasis.     

The effect of power frequency high intensity electric fields on implanted cardiac pacemakers

Thirty-five patients fitted with 16 different pacemaker models (from 6 manufacturers) were exposed to 50 Hz electric fields up to a maximum of 20 kV/m. Four different response patterns were encountered: (1) normal sensing and pacing in all Medtronic and some Vitatron units; (2) reversion to the fixed (interference) rate in all Telectronics, all Pacesetter, some Vitatron and CPI units; (3) slow and irregular pacing in one CPI and in all Cordis units; (4) mixed behavior over a critical range of field strengths in which slow and irregular pacing preceded reversion to fixed-rate, in some Telectronics and Pacesetter units. The field strengths required to induce such behavior varied from unit to unit and from model to model, with Telectronics being the most sensitive. In general, the interference threshold depended on the magnitude and distribution of induced body current relative to the pacemaker as well as field strength and thus varied with patient height, build and posture. While only a small proportion of pacemaker patients are likely to encounter electric fields strong enough to interfere with pacemaker behavior, this possible hazard should be recognized.     

No immediate analgesic effect of diadynamic current in patients with nonspecific low back pain in comparison to TENS

Background and design

Chronic nonspecific low back pain (CNSLBP) has major socioeconomic as well as personal impact in many industrialized and developing countries. Physiotherapy is a common intervention for this group of patients and using anti-pain physical modalities is a common part of the physical therapy. In a randomized controlled trial we investigated the immediate effect of the Diadynamic current in comparison to TENS on reducing the pain in patients suffering from non specific chronic low back pain.

Embryotoxic and teratogenic effect of high intensity, low frequency ultrasonic vibration on chicken embryos

Controlled exposure of chicken embryos to continuous 30 W/cm², 29 kHz ultrasonic vibration in a water medium produced, in proportion to exposure, progressively retarded growth or death. Analysis supports, and observation confirms, the presence of cavitation in the water medium. The effects reported here differ substantially from published observations of megaHertz insonation of chicken embryos at similar intensities. The experiments closely resemble in method of application, frequency and intensity the operation of several ultrasonic surgical and dental instruments.     

中等强度持续运动与高强度间歇运动对预防高脂膳食大鼠心肌和比目鱼肌脂质沉积效果的研究

摘要 目的：探讨中等强度持续运动（moderate intensity continuous training,MICT）与高强度间歇运动（high intensity interval training,HIIT）预防高脂膳食大鼠心肌和比目鱼肌脂质沉积的效果及机制。 方法：32只雄性SD大鼠随机分为正常膳食对照组（C）、高脂膳食对照组（F）、高脂膳食MICT组（M）、高脂膳食HIIT组（H）。M组大鼠进行70%VO2max强度的跑台持续运动,H组大鼠进行以40%—45%VO2max和95%—99%VO2max强度交替的跑台运动,确保两组大鼠跑动距离相同。透射电镜观察心肌和比目鱼肌超微结构;检测血清FFA、TG、HDL、LDL含量;Western Blot检测心肌和比目鱼肌NAMPT、AMPK蛋白表达。 结果：与C组比较,F组心肌与比目鱼肌脂质沉积增加,M组比目鱼肌脂质沉积较H组少,H组心肌脂质沉积较M组少;与C组比较,F组大鼠血清LDL、TG和FFA增加（n=8,P＜0.05）;M、H组血清LDL、FFA较F组降低（n=8,P＜0.01）;H组血清HDL较M组增加（n=8,P＜0.01）;与C组比较,F组大鼠心肌、比目鱼肌NAMPT、AMPK蛋白表达升高（n=8,P＜0.05）,M、H组较F组增加（n=8,P＜0.01）,H组心肌NAMPT、AMPK较M组增加（n=8,P＜0.01）,H组比目鱼肌NAMPT、AMPK较M组降低（n=8,P＜0.01）。 结论：MICT和HIIT可通过NAMPT、AMPK预防心肌、比目鱼肌脂质沉积,且MICT预防比目鱼肌脂质沉积效果较好,HIIT预防心肌脂质沉积效果较好。     

1例嗅神经母细胞瘤患者调强适形放射治疗的护理

嗅神经母细胞瘤是较少见的头颈部恶性肿瘤之一。通过手术和放射治疗可降低其局部复发率0%～40%,5年生存率最高达67%,是嗅神经母细胞瘤最有效的治疗手段[1]。调强适形放射治疗(intensity modulated radiation therapy,IMRT)是目前放射治疗最先进的技术,它以直线加速器为     

Chronopharmacology of analgesic effect and its tolerance induced by morphine in mice

The influence of morphine dosing time on analgesic effect after acute or chronic treatment, recovery of analgesic effect after once developed tolerance, and their pharmacological mechanisms were investigated in ICR male mice under a 12-h light/dark cycle (light on from 7:00 AM to 7:00 PM). There was a significant 24-h rhythm in the latency of thermal response at 30 min after morphine injection. The analgesic effect was significantly greater at the dark phase than at the light phase. The rhythmic pattern resembled overall the rhythm occurring in the latency of thermal response under non-drugged state. The absolute value of morphine analgesic effect (the real time spent on the hot-plate) on days 1 and 2 after morphine daily injection was significantly larger after morphine injection at 9:00 PM than after saline injection at 9:00 PM or after morphine injection at 9:00 AM. The recovery from tolerance of analgesic effect was significantly faster at the dark phase than at the light phase. The time-dependent difference in the analgesic effect after chronic treatment or recovery from tolerance is closely related to that in the expression of mu-opioid receptor. The present study suggests that 24-h rhythm of morphine analgesic effect is consistent with 24-h rhythm of mu-opioid receptor expression.