下行易化系统及其参与神经病理痛的机制

神经病理痛是指由中枢或外周神经系统损伤或疾病引起的疼痛综合征.神经病理痛是临床上常见的一种疾病,但是其发病机制不甚清楚,临床上也缺乏有效的治疗手段.近年来的研究除了集中于痛觉的上行传导及中枢机制,以及痛觉的下行抑制之外,也证明下行易化系统激活参与神经病理痛的发病机制.本文拟对此进行综述,希望为治疗神经病理痛提供新思路.     

Brain mechanisms of pain affect and pain modulation

Recent animal studies reveal ascending nociceptive and descending modulatory pathways that may contribute to the affective-motivational aspects of pain and play a critical role in the modulation of pain. In humans, a reliable pattern of cerebral activity occurs during the subjective experience of pain. Activity within the anterior cingulate cortex and possibly in other classical limbic structures, appears to be closely related to the subjective experience of pain unpleasantness and may reflect the regulation of endogenous mechanisms of pain modulation.     

内源性下行抑制/易化系统与5-羟色胺对脊髓伤害感受性信息的调制

内源性下行抑制系统在痛传递与调制中具有重要作用。近年来,与这一系统相对的下行易化系统开始引起人们的关注。中枢神经系统通过下行抑制易化系统对外周伤害性信息进行双向调制。５－羟色胺（５－ＨＴ）是痛上行调制系统的主要神经递质,电刺激或微量注射兴奋性氨基酸于中缝大核（ＮＭＲ）或巨细胞网状核（ＮＧＣ）内,既可兴奋也可抑制脊髓伤害性反应。这种相互矛盾遥效应可能与脊髓内的多种５－ＨＴ受体亚型有关。     

Dysregulation of the Descending Pain System in Temporomandibular Disorders Revealed by Low-Frequency Sensory Transcutaneous Electrical Nerve Stimulation: A Pupillometric Study

Using computerized pupillometry, our previous research established that the autonomic nervous system (ANS) is dysregulated in patients suffering from temporomandibular disorders (TMDs), suggesting a potential role for ANS dysfunction in pain modulation and the etiology of TMD. However, pain modulation hypotheses for TMD are still lacking. The periaqueductal gray (PAG) is involved in the descending modulation of defensive behavior and pain through μ, κ, and δ opioid receptors. Transcutaneous electrical nerve stimulation (TENS) has been extensively used for pain relief, as low-frequency stimulation can activate µ receptors. Our aim was to use pupillometry to evaluate the effect of low-frequency TENS stimulation of μ receptors on opioid descending pathways in TMD patients. In accordance with the Research Diagnostic Criteria for TMD, 18 females with myogenous TMD and 18 matched-controls were enrolled. All subjects underwent subsequent pupillometric evaluations under dark and light conditions before, soon after (end of stimulation) and long after (recovery period) sensorial TENS. The overall statistics derived from the darkness condition revealed no significant differences in pupil size between cases and controls; indeed, TENS stimulation significantly reduced pupil size in both groups. Controls, but not TMD patients, displayed significant differences in pupil size before compared with after TENS. Under light conditions, TMD patients presented a smaller pupil size compared with controls; the pupil size was reduced only in the controls. Pupil size differences were found before and during TENS and before and after TENS in the controls only. Pupillometry revealed that stimulating the descending opioid pathway with low-frequency sensory TENS of the fifth and seventh pairs of cranial nerves affects the peripheral target. The TMD patients exhibited a different pattern of response to TENS stimulation compared with the controls, suggesting that impaired modulation of the descending pain system may be involved in TMD.     

丘脑中央下核在痛觉感受与痛觉调制中的作用

本结合笔的工作,综述了近年来关于丘脑中央下核（Ｓｍ）在痛觉感受与痛觉调制中作用的研究。结果表明,它可能主要与痛觉的情绪激动成分有关,而且Ｓｍ－ＶＬＯ－ＰＡＧ可能构成一个痛觉调制的通路,通过脑干下行抑制系统在脊髓水平调制伤害感受性输入,从而产生痛觉的负反馈性调节。     

神经递质和调质参与导水管周围灰质痛觉调控的研究进展

导水管周围灰质(periaqueductal gray,PAG)在疼痛的调控过程中处于一个不可或缺的位置.其不仅是痛觉信息上行传递的重要部位,还是疼痛抑制系统的重要组成部分.在PAG,包括γ-氨基丁酸(γ-aminobutyric acid,GABA)、5-羟色胺(5-hydroxytryptamine,5-HT)和谷氨酸(glutamate,Glu)在内的神经递质以及内源性阿片肽(endogenous opioid peptides,EOP)和内源性大麻素(endocannabinoid,e CB)为代表的神经调质都参与了PAG对疼痛的信息传递以及调节.本文重点综述GABA、5-HT、Glu、EOP和eCB在PAG参与疼痛生理调控机制的研究进展,以期为中枢神经系统的镇痛研究提供一定的理论基础.     

Paradoxical Sleep Deprivation Aggravates and Prolongs Incision-Induced Pain Hypersensitivity via BDNF Signaling-Mediated Descending Facilitation in Rats

The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not fully established. The modulation of BDNF signaling-mediated descending facilitation from the rostral ventromedial medulla (RVM) of brain stem has been demonstrated in persistent pain models of inflammatory pain, but not in incisional pain model. Recent study has shown that PSD increases the expression of brain-derived neurotrophic factor (BDNF) in the brainstem structure. Therefore, in the current study, we asked whether the BDNF signaling-mediated descending facilitation was involved in the PSD-induced pronociceptive effect on incisional pain and delay the recovery period of postoperative pain in rats. Our results found that a preoperative 24 h PSD significantly aggravated the pain hypersensitivity after incision and prolonged the duration of postoperative pain. The lesions of ipsilateral dorsolateral funiculus partly reversed the PSD-induced pronociceptive effect on incisional pain. Interestingly, the 24 h PSD, but not incision significantly enhanced the levels of BDNF protein expression in the RVM areas of rats. Furthermore, at 1 day or 4 days after incision, intra-RVM microinjection of a BDNF antibody partly reversed the PSD-induced pronociceptive effects in incisional rats, while it did not change the cumulative pain scores and paw withdrawal thresholds in rats receiving only plantar incision. These findings suggest that the preoperative PSD may aggravate and prolong the incision-induced pain hypersensitivity via BDNF signaling-mediated descending facilitation.     

主动运动和被动运动的镇痛效果及其镇痛机制

主动运动和被动运动可以有效缓解各种急性疼痛和慢性疼痛,且主动运动诱发的镇痛效果强于运动参数相似的被动运动.文章在讨论运动镇痛机制的基础上,探讨了主、被动运动镇痛效果存在差异的原因.具体来说,通过比较两种运动传导运动信息的下行通路和传导躯体感觉/本体感觉的上行通路,论述了主、被动运动在生理(外周神经系统和中枢神经系统)和心理(情绪和认知)层面上镇痛机制的异同.由于被动运动缺少运动下行控制且肌肉激活程度小,其在外周镇痛物质含量和皮层水平上对疼痛的调控弱于主动运动.此外,被动运动相比主动运动不易诱发积极情绪,较难转移对疼痛的注意力,缺乏身体掌控感并拥有较低的身体归属感,进而导致较弱的镇痛效果.最后,文章指出了目前本领域研究的局限性,并对运动镇痛未来的研究方向和方法提出了建议.     

Pain hypersensitivity mechanisms at a glance

There are two basic categories of pain: physiological pain, which serves an important protective function, and pathological pain, which can have a major negative impact on quality of life in the context of human disease. Major progress has been made in understanding the molecular mechanisms that drive sensory transduction, amplification and conduction in peripheral pain-sensing neurons, communication of sensory inputs to spinal second-order neurons, and the eventual modulation of sensory signals by spinal and descending circuits. This poster article endeavors to provide an overview of how molecular and cellular mechanisms underlying nociception in a physiological context undergo plasticity in pathophysiological states, leading to pain hypersensitivity and chronic pain.     

Activation of ERK signaling in rostral ventromedial medulla is dependent on afferent input from dorsal column pathway and contributes to acetic acid-induced visceral nociception

Several lines of evidence from both animal and clinical studies have demonstrated that dorsal column (DC) pathway plays a critical role in visceral pain transmission from the spinal cord to supraspinal center. The descending pain modulation pathway from the rostral ventromedial medulla (RVM) area has been implicated in visceral nociceptive neurotransmission. Previous studies have demonstrated that the multiple protein kinase signaling transduction cascades in the RVM area contribute to the descending facilitation of inflammatory pain and neuropathic pain. However, whether these signaling transduction pathways in the RVM area are triggered by the afferent visceral input from the DC pathway during acute visceral pain remains elusive. Here, we have tested the hypothesis that the afferent visceral stimuli from the DC pathway might induce the activation of extracellular signal-regulated protein kinase (ERK) signaling in the RVM area and contribute to the descending facilitation of neurotransmission in a rat model of visceral pain. Our results showed that acetic acid-induced visceral nociception produced a persistent activation of ERK in the RVM area and a microinjection of a mitogen-activated ERK kinase (MEK) inhibitor, U0126, into the RVM area significantly inhibited the visceral noxious stimulation-induced behaviors in rats. A microinjection of lidocaine into the nucleus gracilis (NG) also inhibited the activation of ERK in the RVM area. The current study indicates that activated ERK signaling pathway in the RVM area is dependent on afferent input from dorsal column pathway and may contribute to acetic acid-induced visceral nociception.     

The cerebral signature for pain perception and its modulation

Our understanding of the neural correlates of pain perception in humans has increased significantly since the advent of neuroimaging. Relating neural activity changes to the varied pain experiences has led to an increased awareness of how factors (e.g., cognition, emotion, context, injury) can separately influence pain perception. Tying this body of knowledge in humans to work in animal models of pain provides an opportunity to determine common features that reliably contribute to pain perception and its modulation. One key system that underpins the ability to change pain intensity is the brainstem's descending modulatory network with its pro- and antinociceptive components. We discuss not only the latest data describing the cerebral signature of pain and its modulation in humans, but also suggest that the brainstem plays a pivotal role in gating the degree of nociceptive transmission so that the resultant pain experienced is appropriate for the particular situation of the individual.     

Interictal Dysfunction of a Brainstem Descending Modulatory Center in Migraine Patients

Background

The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks, either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an attack (i.e. the interictal phase).

Methods and Findings

Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41°C and noxious heat (pain threshold+1°C). Stimuli were either applied to the forehead on the affected side (as reported during an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed significantly greater NCF activation in control subjects than the migraine patients.

Conclusions

Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the evaluation of therapies for migraine.     

Role of the RVM in Descending Pain Regulation Originating from the Cerebrospinal Fluid-Contacting Nucleus

Evidence has suggested that cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is correlated with the development and recurrence of pain. A recent research showed that the CSF-contacting nucleus acts as a component of the descending 5-hydroxytryptamine (5-HT) system and plays a role in descending pain inhibition. However, limited studies are conducted to investigate the relationship between the CSF-contacting nucleus and pain. In present study, we explored the effect of CSF-contacting nucleus on nociceptive behaviors in both normal and neuropathic rats via targeted ablation of the CSF-contacting nucleus in the brainstem, using cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The CB-SAP-treated rats showed aggravated thermal hyperalgesia and mechanical allodynia. Also, results from immunohistochemical experiments showed that rostral ventromedial medulla (RVM) received fiber projection from the CSF-contacting nucleus, which disappeared after ablation of the CSF-contacting nucleus, and the CB-SAP treated rats showed downregulation of c-Fos expression in the RVM as compared with the rats receiving i.c.v. injection of phosphate buffer saline (PBS). A significant downregulation of 5-HT-labeled neurons and tryptophan hydroxylase 2 (TPH2) as the marker of 5-HT cells in the RVM, and 5-HT expression in spinal dorsal horn in both normal and chronic constriction injury (CCI) rats after i.c.v. injection of CB-SAP was observed. These results suggested that RVM may be involved in descending pain modulation originating from the CSF-contacting nucleus.     

TRPV1通道在中枢神经系统中的功能

TRPV1（transient receptor potential vanilloid 1）是在机体广泛分布的非选择性阳离子通道,能被氢离子、高温以及其它内源性和外源性配体激活.其在外周神经系统中主要参与伤害性高温的感受以及痛觉过敏等生理机制.TRPV1在中枢神经系统中功能的研究进展主要体现在突触传递,体温调节,痛觉的调制和细胞凋亡等方面.TRPV1的激活降低突触前谷氨酸的释放及增强已存在的突触后AMPA受体的作用,从而增强了突触传递效能.外周的TRPV1通过激活能够抑制血管的收缩和生热作用,从而抑制体温的升高,当TRPV1被阻断时就发生体温过高,而TRPV1体温调节的中枢作用机制可能是通过直接作用于体温调节中枢.脑干的痛觉调制环路的激活TRPV1可以引起谷氨酸盐的释放,进而激活突触后I类mGlu受体以及NMDA受体,从而起到镇痛的功能.另外近年发现TRPV1在中枢也参与呕吐、呼吸、心率及血压的调节.     

Neurobiology of pain

The neurobiology of pain had a notable interest in research focused on the study of neuronal plasticity development, nociceptors, molecular identity, signaling mechanism, ionic channels involved in the generation, modulation and propagation of action potential in all type of excitable cells. All the findings open the possibility for developing new therapeutic treatment. Nociceptive/inflammatory pain and neuropathic pain represent two different kinds of persistent chronic pain. We have reviewed the different mechanism suggested for the maintenance of pain, like descending nociceptive mechanism and their changes after tissue damage, including suppression and facilitation of defence behavior during pain. The role of these changes in inducing NMDA and AMPA receptors gene expression, after prolonged inflammation is emphasized by several authors. Furthermore, a relation between a persistent pain and amygdale has been shown. Molecular biology is the new frontier in the study of neurobiology of pain. Since the entire genome has been studied, we will able to find new genes involved in specific condition such as pain, because an altered gene expression can regulate neuronal activity after inflammation or tissue damage.     

Sensorimotor and Pain Modulation Brain Abnormalities in Trigeminal Neuralgia: A Paroxysmal,Sensory-Triggered Neuropathic Pain

Objective

Idiopathic trigeminal neuralgia (TN) is characterized by paroxysms of severe facial pain but without the major sensory loss that commonly accompanies neuropathic pain. Since neurovascular compression of the trigeminal nerve root entry zone does not fully explain the pathogenesis of TN, we determined whether there were brain gray matter abnormalities in a cohort of idiopathic TN patients. We used structural MRI to test the hypothesis that TN is associated with altered gray matter (GM) in brain areas involved in the sensory and affective aspects of pain, pain modulation, and motor function. We further determined the contribution of long-term TN on GM plasticity.

Methods

Cortical thickness and subcortical GM volume were measured from high-resolution 3T T1-weighted MRI scans in 24 patients with right-sided TN and 24 healthy control participants.

Results

TN patients had increased GM volume in the sensory thalamus, amygdala, periaqueductal gray, and basal ganglia (putamen, caudate, nucleus accumbens) compared to healthy controls. The patients also had greater cortical thickness in the contralateral primary somatosensory cortex and frontal pole compared to controls. In contrast, patients had thinner cortex in the pregenual anterior cingulate cortex, the insula and the orbitofrontal cortex. No relationship was observed between GM abnormalities and TN pain duration.

Conclusions

TN is associated with GM abnormalities in areas involved in pain perception, pain modulation and motor function. These findings may reflect increased nociceptive input to the brain, an impaired descending modulation system that does not adequately inhibit pain, and increased motor output to control facial movements to limit pain attacks.     

Dissociable Neural Mechanisms Underlying the Modulation of Pain and Anxiety? An fMRI Pilot Study

The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a “behavioral control” paradigm, which involves the ability to terminate a noxious stimulus, and a “safety signaling” paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.     

The effects of intraspinal L-NOARG or SIN-1 on the control by descending pathways of incisional pain in rats

The modulation by spinal nitric oxide (NO) of descending pathways travelling through the dorsal lateral funiculus (DLF) is a mechanism proposed for the antinociceptive effects of drugs that changes the NO metabolism. In this study we confirm that a surgical incision in the mid-plantar hind paw of rats reduces the threshold to mechanical stimulation with von Frey filaments. The incisional pain was further increased in rats with ipsilateral DLF lesion. Intrathecal L-NOARG (50-300 microg), or SIN-1 (0.1-5.0 microg) reduced, while SIN-1 (10 and 20 microg) intensified the incisional pain in rats with sham or effective lesion of the DLF. Stimulation of the dorsal raphe (DRN) or anterior pretectal (APtN) nuclei with stepwise increased electrical currents (7, 14, 21, 28 and 35 microA r.m.s.) produced a current-related reduction of the incisional pain. These nuclei activate pain inhibitory pathways that descend to the spinal cord mainly through the DLF. Intrathecal SIN-1 (5 microg) reduced, SIN-1 (20 microg) decreased and L-NOARG (150 microg) did not change the EC50 for the DRN or APtN stimulation-induced reduction of incisional pain. We conclude that the antinociceptive effects of L-NOARG or low doses of SIN-1 are independent on the activity of descending pain control pathways travelling via the DLF, but the antinociceptive effect of stimulating electrically the DRN or APtN can be summated to the effect of low dose of SIN-1 or overcome by the high dose of SIN-1.     

Pain pathways and transmission.

Pain has been a major concern of humankind since the ancient times, and it remains one of the most important subjects of all health care professionals. Despite the obvious overwhelming clinical importance, the major advances in its diagnosis and therapy have been made only recently. "How do the sensory apparatus of the body and system of signal transmission relate to pain of peripheral origin?" is the topic of discussion. To do this, it is important to understand what constitutes the total pain experience. It consists of: 1) signal transduction at the peripheral receptor site, 2) signal conduction along the peripheral nerve, 3) pain modulation at the level of the spinal cord, 4) pain perception at the supraspinal site, and 5) the associated sensations, emotional reactions, and effective state. The signal transmission related to pain may be modified by various analgesic agents. Specific analgesic agent has a specific site of action which may be at peripheral receptors, at peripheral nerves, at the level of the spinal cord, at supraspinal levels by activating descending inhibitory systems, or at more cephalad levels by reducing the affective component of pain.     

电刺激和损毁丘脑中央下核对大鼠福尔马林诱发伤害性行为的影响

本文旨在研究丘脑中央下核（thalamic nucleus submedius,Sm）是否参与持续伤害感受性调制。以自动运动检测系统记录大鼠一侧后爪皮下注射福尔马林诱发的伤害性行为（烦乱反应）为指标,观察电刺激和电解损毁Sm对烦乱反应的效应。结果显示,电刺激（100μA,5min）同侧或对侧Sm明显抑制福尔马林诱发的第二时相的烦乱反应,而刺激Sm外邻近结构（超过0．5mm）对烦乱反应无明显效应。电解损毁双侧Sm对第一或第二时相的烦乱反应均无影响。结果提示,Sm不仅参与急性时相性伤害感受性调制,也参与持续性伤害感受性调制。本研究为Sm参与下行痛调制提供了新的证据。