每周论文更新----30 Sep 2016

zhouxuelong0258

每周论文更新----30 Sep 2016
周伯通博士
由于没有新的文献更新，所以我们这周做了一期疼痛经典（里程碑式的）文章回顾。这些经典论文可能在你们的论文引用中出现过很多次，但是真正知道并看过这些文章的却并不是很多。因此，我们费了一些力气，将这些经典的论文收集了起来，在本期中推送给大家。当中可能会有一些经典论文没有被收录，有知道的请告知于我们，我们将在以后的论文更新中推送给大家。

首先，我们推送的是Melzack和Wall于20世纪60年代提出的关于闸门控制学说理论的文献。闸门控制学说提出之前，疼痛的研究更倾向于解剖学研究。它的提出让疼痛研究真正成为一门单独的科学研究，并且为现代疼痛理论的提出（包括疼痛的下行抑制系统以及中枢敏化理论等）提供了重要的理论基础。

On the nature of cutaneous sensory mechanisms.

Melzack R, Wall PD.

Brain. 1962 Jun

PMID: 14472486

Pain mechanisms: a new theory.

Melzack R, Wall PD.

Science. 1965 Nov 19

PMID: 5320816

初级神经元或者称作背根神经节神经元存在很多一系列的表型，包括大直径、中小直径的神经元等，其神经纤维表现出来有髓神经纤维以及无髓神经纤维等。下面的这两篇文献揭示了传递痛觉的初级神经元的神经纤维为无髓神经纤维，将其同传递触觉的有髓神经纤维分离开来。

Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibers.

Mendell LM, Wall PD.

Nature. 1965 Apr 3

PMID: 14334366

Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.

Christensen BN, Perl ER.

J Neurophysiol. 1969 Nov

PMID: 5415075

Rexed于20世纪50年代在猫的身上将脊髓分为10个板层，下面的这篇文献揭示了介导疼痛的为脊髓背角的外板层，也就是我们常说的I板层和II板层。

Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn.

Christensen BN, Perl ER.

J Neurophysiol. 1970 Mar

PMID: 5415075

下面的这四篇都是研究疼痛的下行抑制系统（内源性阿片肽）的文献，下行抑制系统的发现为闸门控制学说提供了重要的实验验证。

Analgesia induced by electrical stimulation of the inferior centralis nucleus of the raphe in the cat.

Oliveras JL, Redjemi F, Guilbaud G, Besson JM.

Pain. 1975 Jun

PMID: 1088446

Abstract

In the cat, electrical stimulation of the inferior central nucleus of the raphe induces a powerful analgesia. This stimulation totally suppresses the behavioural reactions elicited by strong pinches applied to the tail or to the four limbs; it strongly modifies the threshold of the jaw opening reflex obtained by tooth pulp stimulation and considerably affects the behavioural reactions elicited by continuing such stimulation. The results can be considered as evidence that the mechanism of analgesia from the inferior raphe nucleus is similar to that already described in the dorsal raphe nucleus. The analgesia obtained by stimulation of raphe nuclei seems to be sustained by serotoninergic mechanisms and relationships between these are discussed. In preliminary experiments, analgesia induced by CI stimulation has been suppressed by administration of naloxone, a specific opiate antagonist.

Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist.

Akil H, Mayer DJ, Liebeskind JC.

Science. 1976 Mar 5

PMID: 1251210

Abstract

Analgesia produced by focal electrical stimulation of the brain is partially reversed by the narcotic antagonist naloxone. The absence of complete reversal does not appear to be caused by inadequate doses of naloxone since doses higher than 1 milligram per kilogram of body weight did not increase the antagonism. It is suggested that stimulation-produced analgesia may result, at least in part, from release of an endogenous, narcotic-like substance, such as that recently reported by other investigators.

Opiate and stimulus-produced analgesia: functional anatomy of a medullospinal pathway.

Basbaum AI, Clanton CH, Fields HL.

Proc Natl Acad Sci U S A. 1976 Dec

PMID: 1070018

Abstract

Neurons in ventromedial medulla, including the nucleus raphe magnus, project to trigeminal nucleus caudalis and, via the dorsolateral funiculus, to spinal dorsal horn. The terminals of this descending system are in loci containing cells responsive to noxious stimuli. Electrical stimulation of nucleus raphe magnus selectively inhibits spinal dorsal horn neurons that respond to noxious stimuli. These neurons are located near the anatomically demonstrated terminals of this descending system. Dorsolateral funiculus lesions block this descending inhibition of spinal neurons as well as the analgesic action of morphine. This evidence supports the hypothesis that this neuron population mediates the analgesia produced by opiates and electrical stimulation of certain diencephalic and brainstem sites.

Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone.Hosobuchi Y, Adams JE, Linchitz R.

Science. 1977 Jul 8

PMID: 301658

Abstract

Relief of intractable pain was produced in six human patients by stimulation of electrodes permanently implanted in the periventricular and periaqueductal gray matter. The level of stimulation sufficient to induce pain relief seems not to alter the acute pain threshold. Indiscriminate repetitive stimulation produced tolerance to both stimulation-produced pain relief and the analgesic action of narcotic medication; this process could be reversed by abstinence from stimulation. Stimulation-produced relief of pain was reversed by naloxone in five out of six patients. These results suggest that satisfactory alleviation of persistent pain in humans may be obtained by electronic stimulation.

这是第一篇介绍安慰剂通过内源性阿片肽产生镇痛效应的文章。

The mechanism of placebo analgesia.Levine JD, Gordon NC, Fields HL.

Lancet. 1978 Sep 23

PMID: 80579

Abstract

The effect of naloxone on dental postoperative pain was studied to examine the hypothesis that endorphins mediate placebo analgesia. All patients had extraction of impacted mandibular third molars with diazepam, N2O, and local block with mepivacaine. 3 h and 4 h after surgery naloxone or a placebo was given under randomised, double-blind conditions. Pain was evaluated on a visual analogue scale. Patients given naloxone reported significantly greater pain than those given placebo. Patients given placebo as their first drug was either placebo responders, whose pain was reduced or unchanged, or nonresponders whose pain increased. Naloxone given as a second drug produced no additional increase in pain levels in nonresponders but did increase pain levels of placebo responders. Nonresponders had a final mean pain rating identical to that of responders who received naloxone as their second drug. Thus the enhancement of reported pain produced by naloxone can be entirely accounted for by its effect on placebo responders. These data are consistent with the hypothesis that endorphin release mediates placebo analgesia for dental postoperative pain.

现在最耳熟能详的中枢敏化理论的提出。

Evidence for a central component of post-injury pain hypersensitivity.

Woolf CJ.

Nature. 1983 Dec 15

PMID: 6656869

Abstract

Noxious skin stimuli which are sufficiently intense to produce tissue injury, characteristically generate prolonged post-stimulus sensorydisturbances that include continuing pain, an increased sensitivity to noxious stimuli and pain following innocuous stimuli. This could result from either a reduction in the thresholds of skin nociceptors (sensitization) or an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses. Because sensitization of peripheral receptors occurs following injury, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes.

第一篇介绍ACC脑区编码疼痛信息的文章，现在做的最多的为多伦多大学的卓敏院士团队。

Pain affect encoded in human anterior cingulate but not somatosensory cortex.

Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC.

Science. 1997 Aug 15

PMID: 9252330

Abstract

Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.

最后这一篇不用说，能得诺奖的文章。

The capsaicin receptor: a heat-activated ion channel in the pain pathway.

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D.

Nature. 1997 Oct 23

PMID: 9349813

Abstract

Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.

对于2000年以后的文章，真正做到能够对疼痛研究起到非常重要推动作用的文章不多，TRPV1离子通道结构解析的文章算是一篇，但是其他的文章对于整个疼痛研究的推进的作用着实不算大，这里就不列举了。

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