Considerations concerning the neurobiological basis of muscle pain

Nociceptors in skeletal muscle can be sensitized by substances that are released from pathologically altered tissue. In the sensitized state, nociceptors can be activated by low-intensity stimulation; this is probably one of the mechanisms producing deep tenderness. Dorsal horn cells processing input from muscle nociceptors often have multiple receptive fields and additional input from other deep tissues or skin. This may be one of the reasons for the diffuse and ill-localized nature of muscle pain. The degree of convergence from deep tissues and skin in neurones with muscle input can be increased by noxious stimulation of deep tissues. This mechanism might explain phenomena such as spread and referral of muscle pain. In the development of chronic muscle pain, vicious circles may be involved which operate locally in the damaged tissue or via spinal reflexes that alter the biochemical environment of the nociceptors in skeletal muscle.     

Electrical stimulation of peripheral and central pathways for the relief of musculoskeletal pain

One method for the treatment of chronic musculoskeletal pain involves stimulation of the peripheral or central nervous system. Such stimulation includes transcutaneous electrical nerve stimulation, dorsal column stimulation, and deep brain stimulation. This review discusses the clinical use of electrical stimulation for the relief of musculoskeletal pain, and describes the results of studies conducted in our laboratory suggesting that such stimulation reduces pain transmission along sensory-discriminative pathways.     

经颅电刺激镇痛研究的现状及展望

经颅电刺激技术是一种非侵入性神经调控方法,因其具有卓越的安全性、良好的患者依从性以及高度便携性等特点,被视为一种潜在的非药物镇痛手段。然而,目前对于经颅电刺激镇痛效果的研究结果不一致且镇痛机制尚未完全阐明。本文通过系统归纳总结3种主要的经颅电刺激技术——经颅直流电刺激、经颅交流电刺激和经颅随机噪声刺激——在镇痛领域的研究进展,评估了这些技术对短时、急性和慢性疼痛的镇痛效果,并深入剖析了其潜在的镇痛机制。同时,本文系统讨论了既往研究的局限性,并对未来研究提出了一系列切实可行的建议,如借助电场模拟技术实现个性化刺激以克服不同个体头部解剖结构差异的影响、应用多位点刺激和深部脑刺激技术来拓展刺激脑区、搭建经颅电刺激技术同步神经影像平台以制定个体特异性的刺激方案并深入揭示其镇痛机制、探索与其他治疗技术的联合应用以提高疗效等。这些建议的实施将有助于解决当前研究中存在的问题,充分发挥经颅电刺激在疼痛治疗中的临床价值,最终实现患者疼痛的缓解。     

Effects of ethanol on deep pain evoked by formalin injected in TMJ of rat

It has been reported that ethanol can alter nociceptive sensitivity from superficial tissues, such as skin and subcutaneous region. However, the influence of ethanol on deep pain conditions is not understood. The aim of this study was to demonstrate the acute, chronic and ethanol withdrawal effects on nociceptive behavioral responses induced by the injection of formalin into the temporomandibular joint (TMJ) region of rats. In experiment 1, rats were injected with ethanol (2,5 g/Kg, i.p.) or an equal volume of saline 15 min before the administration of formalin (1.5%) into the TMJ. Rats pretreated with ethanol showed a decrease in nociceptive behavioral responses. In experiment 2, rats were given an ethanol solution (6.5%) or tap water to drink for 4 and 10 days. On day 4, the animals (ethanol group) showed amounts of analgesia when submitted to the TMJ formalin test. Tolerance to the antinociceptive effects was observed on day 10. Behavioral hyperalgesia was verified 12 hr after withdrawal in another group that drank ethanol for 10 days. These results show that ethanol can affect the nociceptive responses related to deep pain evoked by the TMJ formalin test.     

Thalamic stimulation effects on reactive depression

Depression was evaluated in 10 patients before and after therapeutic mesothalamic brain stimulation for chronic pain. Minnesota multiphasic personality inventory T scores for depression were high in all patients before stimulation. Scores were decreased in 8 of 10 patients with chronic deep brain stimulation, three of whom returned to normal. Pain relief was good to excellent in 9 of 10 patients. It is concluded that depression is secondary to pain or pain-inducing factors which implicate the catecholamine and serotonergic systems.     

Paradoxical experience of hypnotic analgesia in low hypnotizable fibromyalgic patients

The study investigated the differences in pain perception in highly (Highs) and low (Lows) hypnotizable patients with chronic benign pain undergoing hypnotic suggestions of analgesia. Self reports of pain intensity were collected in different groups of fibromyalgic patients: (1) Highs and Lows during pre-hypnosis, neutral hypnosis, suggestions for analgesia, posthypnotic conditions; (2) Lows during suggestions for analgesia administered after a mental stress instead of neutral hypnosis; (3) healthy Lows receiving nociceptive stimulation during hypnotic relaxation and suggestions of analgesia. The results showed that Highs and Lows differed in their response to suggestions, but significant analgesia was reported also by Lows. These individuals did not report any difference in pain perception between the sessions including mental stress and hypnotic relaxation. No change in pain perception was observed in healthy Lows during nociceptive stimulation associated with relaxation and suggestions for analgesia. In conclusion, the presence of chronic pain seems to be responsible for the paradoxical response of non hypnotizable patients to hypnotic suggestions.     

Investigation on cerebrospinal fluid opioids and neurotransmitters related to spinal cord stimulation

The purpose of this study was to assess the biochemical mechanisms underlying spinal cord stimulation (SCS). Seventeen patients with chronic pain were investigated by measuring cerebrospinal fluid concentrations of endogenous opioids and biogenic amines before and during dorsal column stimulation. Basal cerebrospinal fluid beta-endorphin levels were below the normal range. No significant change of norepinephrine, epinephrine, dopamine, beta-endorphin, beta-lipotropin, or adrenocorticotropic hormone levels were found after SCS. A 50% increase of cerebrospinal beta-endorphin and beta-lipotropin levels occurred in 6 out of 16 patients, namely those where SCS gave the major pain relief. These data confirm the derangement of the endogenous opioid system in chronic pain conditions and suggest that the beta-endorphin response to SCS could have clinical value in predicting the success of treatment.     

Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

ABSTRACT: BACKGROUND: Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the alpha value). We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. FINDINGS: Neuronal activities were recorded with 4 X 8 multichannel electrode arrays in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC). Under light anesthesia, peripheral pinch stimulation increased the slope of the alpha value in both the ACC and S1, whereas brush stimulation increased the alpha value only in the S1. The increase in alpha values was blocked in both regions under deep anesthesia. The increase in alpha values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in alpha values in the S1 induced by brush and pinch stimulation was not affected. CONCLUSIONS: The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The alpha value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.     

Pain—Mechanisms and Management

In the past two decades there has been remarkable progress in understanding the neural mechanisms of pain. However, chronic pain is poorly understood and, by definition, poorly managed. In addition to hyperactivity of the sympathetic nervous system and damage to normal inhibitory mechanisms, social and psychological factors play a major role in producing the disability of chronic pain. New approaches to manage chronic pain include nonopiate drugs, transcutaneous electral nerve stimulation and psychological and behavioral methods. A nervous system network has recently been described that suppresses pain. This analgesic action is mediated by endogenous opioid peptides (endorphins) and by biogenic amines. The analgesia network can be activated either by electral stimulation or by opiates such as morphine or methadone.     

Pain issues in poultry

This review highlights the possible pain experienced by layer and broiler poultry in modern husbandry conditions. Receptors which respond to noxous stimulation (nociceptors) have been identified and physiologically characterised in many different part of the body of the chicken including the beak, mouth, nose, joint capsule and scaly skin. Stimulation of these nociceptors produces cardiovascular and behavioural changes consistent with those seen in mammals and are indicative of pain perception. Physiological and behavioural experiments have identified the problem of acute pain following beak trimming in chicks, shackling, and feather pecking and environmental pollution. Chronic pain is a much greater welfare problem because it can last for long periods of time from weeks to months. Evidence for possible chronic pain is presented from a variety of different conditions including beak trimming in older birds, orthopaedic disease in broiler and bone breakage in laying hens. Experiments on pain in the chicken have not only identified acute and chronically painful conditions but also have provided information on qualitative differences in the pain experienced as well as identifying a cognitive component providing evidence of conscious pain perception.     

Can chronic pain be suppressed despite purported tolerance to narcotic analgesia?

Responsivity to acute nociceptive stimulation and the analgesic response to narcotic drugs was examined in rats exposed to an experimental model of chronic pain, i.e. $\text{Mycobacterium butyricum}$-induced adjuvant arthritis. The major findings are that (i) exposure to chronic pain alone causes hypo-algesia; this hypo-algesia can be attenuated by concurrent narcotics administration; (ii) chronic narcotics administration alone causes hyper-algesia; this hyper-algesia can be attenuated by concurrent exposure to chronic pain; (iii) the tolerance to narcotic analgesia which develops upon chronic narcotics administration in pain-free animals, need not occur in animals concurrently exposed to chronic pain. These findings support a recently proposed hypothesis on pain processing by the central nervous system, and may be suggestive of an effective treatment of chronic pain.     

MEG can map short and long-term changes in brain activity following deep brain stimulation for chronic pain

Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.     

Involvement of peripheral TRPV1 in TMJ hyperalgesia induced by ethanol withdrawal

Ethanol withdrawal increases nociception after the injection of formalin into the rat's temporomandibular joint (TMJ). Little is known about the neurological basis for hyperalgesia induced by ethanol withdrawal, but it has been reported that ethanol can potentiate the response of transient receptor potential vanilloid receptor-1 (TRPV1) in superficial tissues. The present study was designed to test the hypothesis that peripheral TRPV1 could be involved on nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats exposed to chronic ethanol administration and ethanol withdrawal. Behavioral hyperalgesia was verified 12 h after ethanol withdrawal in rats that drank an ethanol solution (6.5%) for 10 days. In another group submitted to the same ethanol regimen, the selective vanilloid receptor antagonist capsazepine (300, 600 or 1200 microg/25 microl) or an equal volume of vehicle were injected into the TMJ regions 30 min before the TMJ formalin test. The local injections of capsazepine reduced the increased nociceptive responses induced by ethanol withdrawal. The effect of capsazepine on rats that did not drink ethanol was not significant. These results indicate that the peripheral TRPV1 can contribute to the hyperalgesia induced by ethanol withdrawal on deep pain conditions.     

Influence of surface anesthesia on the pressure pain threshold measured with different-sized probes

Transcutaneous pressure with pressure probes of arbitrary diameters have been commonly used for measuring the threshold and magnitude of muscle pain, yet this procedure lacks scientific validation. To examine the valid probe dimensions, we conducted physiological experiments using 34 human subjects. Pin-prick pain, pressure pain threshold (PPT) to pressure probes of various diameters, heat pain threshold, and electrical pain threshold of deep tissues were measured before and after application of surface lidocaine anesthesia to the skin surface over the brachioradial muscle in a double-blinded manner. The anesthesia neither affected PPT with larger probes (diameters: 1.6 and 15?mm) nor increased electric pain threshold of deep structures, whereas it diminished pain count in pin-prick test and PPT with a 1.0?mm diameter probe, suggesting that mechanical pain thresholds measured with 1.6 and 15?mm probes reflect the pain threshold of deep tissues, possibly muscle. Pain thresholds to heat did not change after application of the anesthesia. These results suggest that larger pressure probes can give a better estimation of muscular pain threshold.     

Influence of surface anesthesia on the pressure pain threshold measured with different-sized probes

Transcutaneous pressure with pressure probes of arbitrary diameters have been commonly used for measuring the threshold and magnitude of muscle pain, yet this procedure lacks scientific validation. To examine the valid probe dimensions, we conducted physiological experiments using 34 human subjects. Pin-prick pain, pressure pain threshold (PPT) to pressure probes of various diameters, heat pain threshold, and electrical pain threshold of deep tissues were measured before and after application of surface lidocaine anesthesia to the skin surface over the brachioradial muscle in a double-blinded manner. The anesthesia neither affected PPT with larger probes (diameters: 1.6 and 15 mm) nor increased electric pain threshold of deep structures, whereas it diminished pain count in pin-prick test and PPT with a 1.0 mm diameter probe, suggesting that mechanical pain thresholds measured with 1.6 and 15 mm probes reflect the pain threshold of deep tissues, possibly muscle. Pain thresholds to heat did not change after application of the anesthesia. These results suggest that larger pressure probes can give a better estimation of muscular pain threshold.     

Le syndrome douloureux chronique pelvien chez l’homme. Quelle physiopathologie? Quel traitement?

Chronic pelvic pain, in young men or elderly men, has always been a challenge to the medical profession, raising problems of assessment and management. Chronic pelvic pain has a high prevalence, which is underestimated as indicated by the following figures: 4% to 8% of patients consulting chronic pain centres, 15% of patients consulting a urologist for symptoms of chronic prostatitis with alteration of quality of life, 70,000 cases of chronic cystitis per year in the USA. The circumstances of onset are multiple: postoperative, after minor or major trauma or postinfectious, sometimes without any particular aetiology and often in a multifactorial context. The pathophysiology is therefore vague and poorly elucidated, as only about 5% of cases of chronic prostatitis have a bacterial cause. However, any form of stimulation activates pain pathways with neurogenic inflammation followed by central sensitization and modification of neuronal plasticity, and finally chronic refractory pain with organic dysfunction. This mechanism is currently proposed in numerous publications concerning postoperative chronic pelvic pain and refractory cystitis and chronic prostatitis. The pathophysiology of these types of pain is probably therefore neurogenic. In the absence of stimulation, a pudendal nerve tunnel syndrome can be suggested. The treatment of chronic pelvic pain in men can be considered in the following way: aetiological treatment whenever possible, neurogenic medical treatment (tricyclic antidepressants for continuous pain, anticonvulsants for intermittent pain, NMDA receptor antagonists in the case of failure), treatment of organic dysfunction, pudendal nerve analgesic block in the case of suspected tunnel syndrome and global treatment of patient with impaired quality of life. In conclusion, a better pathophysiological approach to these forms of chronic pelvic pain can improve these difficult patients.     

Effect of Chronic Pain on Fentanyl Self-Administration in Mice

The development of opioid addiction in subjects with established chronic pain is an area that is poorly understood. It is critically important to clearly understand the neurobiology associated with propensity toward conversion to addiction under conditions of chronic pain. To pose the question whether the presence of chronic pain influences motivation to self-administer opioids for reward, we applied a combination of rodent models of chronic mechanical hyperalgesia and opioid self-administration. We studied fentanyl self-administration in mice under three conditions that induce chronic mechanical hyperalgesia: inflammation, peripheral nerve injury, and repeated chemotherapeutic injections. Responding for fentanyl was compared among these conditions and their respective standard controls (naïve condition, vehicle injection or sham surgery). Acquisition of fentanyl self-administration behavior was reduced or absent in all three conditions of chronic hyperalgesia relative to control mice with normal sensory thresholds. To control for potential impairment in ability to learn the lever-pressing behavior or perform the associated motor tasks, all three groups were evaluated for acquisition of food-maintained responding. In contrast to the opioid, chronic hyperalgesia did not interfere with the reinforcing effect of food. These studies indicate that the establishment of chronic hyperalgesia is associated with reduced or ablated motivation to seek opioid reward in mice.     

An approach to localizing corneal pain representation in human primary somatosensory cortex

The cornea has been a focus of animal electrophysiological research for decades, but little is known regarding its cortical representation in the human brain. This study attempts to localize the somatotopic representation of the cornea to painful stimuli in human primary somatosensory cortex using functional magnetic resonance imaging (fMRI). In this case study, a subject was imaged at 3T while bright light was presented in a block-design, which either produced pain and blinking (during photophobia) or blinking alone (after recovery from photophobia). Pain and blinking produced precisely localized activations in primary somatosensory cortex and primary motor cortex. These results indicate that noxious stimulation of the cornea can produce somatotopic activation in primary somatosensory cortex. This finding opens future avenues of research to evaluate the relationship between corneal pain and central brain mechanisms relating to the development of chronic pain conditions, such as dry eye-like symptoms.     

Evidence of Heterosynaptic LTD in the Human Nociceptive System: Superficial Skin Neuromodulation Using a Matrix Electrode Reduces Deep Pain Sensitivity

Long term depression (LTD) is a neuronal learning mechanism after low frequency stimulation (LFS). This study compares two types of electrodes (concentric vs. matrix) and stimulation frequencies (4 and 30 Hz) to examine homo- and heterosynaptic effects indirectly depicted from the somatosensory profile of healthy subjects. Both electrodes were compared in a prospective, randomized, controlled cross-over study using 4 Hz as the conditioning LFS compared to 30 Hz (intended sham condition). Quantitative sensory testing (QST) was used to examine 13 thermal and mechanical detection and pain thresholds. Sixteen healthy volunteers (10 women, age 31.0±12.7 years) were examined. Depending on the electrodes and frequencies used a divergent pattern of sensory minus signs occurred. Using LFS the concentric electrode increased thermal thresholds, while the matrix electrode rather increased mechanical including deep pain thresholds. Findings after cutaneous neuromodulation using LFS and a matrix electrode are consistent with the concept of heterosynaptic LTD in the human nociceptive system, where deep pain sensitivity was reduced after superficial stimulation of intraepidermal nerve fibres. Cutaneous neuromodulation using LFS and a matrix electrode may be a useful tool to influence deep pain sensitivity in a variety of chronic pain syndromes.     

TNS-evoked long loop effects.

Local analgesia can be produced by transcutaneous electrical stimulation of peripheral nerves. This is used in the treatment of chronic pain states. Its clinical effectiveness depends on two points; namely (1) the stimulation has to be perceptible, and (2) paresthesias elicited by TNS must be localized in the area of pain. To verify this in healthy subjects we produced an experimental pain by radiant heating of the skin and tested the analgesic effect of TNS. TNS stimuli parameters (duration, amplitude and frequency) were determined so that double blind conditions were given. Stimulation with small rectangular pulses showed the best analgesic effect especially at a stimulation rate of 100 Hz. The stimulation of various nerves showed that most of the analgesic effects depend on spinal level mechanisms but probably long loop effects are involved.