Spinal presynaptic inhibition in pain control

Guo, Da; Hu, Jing

doi:10.1016/j.neuroscience.2014.09.032

Cited by 87 publications

(68 citation statements)

References 125 publications

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“…It has been established that some primary sensory afferents may activate spinal interneurons and release GABA [17]. GABA activates GABA A receptors located in primary afferent terminals and then modulates the afferent input from DRG neurons into nociceptive-specific projection neurons (presynaptic inhibition) [8,9]. Indeed, the activation of spinal GABAergic circuits attenuates nociceptive process [28].…”

Section: Discussionmentioning

confidence: 99%

Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice

Peng

Qiu

et al. 2015

Neuroscience Letters

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Section: Discussionmentioning

confidence: 99%

Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice

Peng

Qiu

et al. 2015

Neuroscience Letters

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“…Since most superficial layer neurons show polysynaptic events upon bicuculline treatment in our hands ("dis-inhibition", see Figures 6B and 6D for examples, and (Torsney and MacDermott, 2006)), it is difficult for us to determine and compare the peak currents of monosynaptic responses with or without bicuculline treatment. Thus, we could not determine the contribution of GABA A receptors (Guo and Hu, 2014;Paul et al, 2012) in this regard. In short, given that most previously characterized classes of DH inhibitory interneurons are located in more superficial DH layers (Lu and Perl, 2003;Todd, 2010;Yasaka et al, 2010), our results provide novel insight into the circuits and functions of deep layer DH inhibitory interneurons.…”

Section: Early Ret+ Ddh Neurons Are a New Functional Class Of Spinal mentioning

confidence: 95%

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

Cui¹,

Miao²,

Liang³

et al. 2016

Neuron

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The gate control theory (GCT) of pain proposes that pain-and touch-sensing neurons antagonize each other through spinal cord dorsal horn (DH) gating neurons. However, the exact neural circuits underlying the GCT remain largely elusive. Here, we identified a new population of deep layer DH (dDH) inhibitory interneurons that express the receptor tyrosine kinase Ret neonatally. These early RET+ dDH neurons receive excitatory as well as polysynaptic inhibitory inputs from touch-and/or pain-sensing afferents. In addition, they negatively regulate DH pain and touch pathways through both pre-and postsynaptic inhibition. Finally, specific ablation of early RET+ dDH neurons increases basal and chronic pain, whereas their acute activation reduces basal pain perception and relieves inflammatory and neuropathic pain. Taken together, our findings uncover a novel spinal circuit that mediates crosstalk between touch and pain pathways and suggest that some early RET + dDH neurons could function as pain "gating" neurons.

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“…Increasing spinal inhibition with intrathecal GABA or by activation of inhibitory interneurons results in an antinociceptive effect, while blocking inhibitory transmission, e.g. by selective ablation of glycinergic dorsal horn interneurons, leads to lowered pain thresholds and the development of hyperalgesia and tactile allodynia 50, 69 . Mechanisms of disinhibition include reduced descending inhibitory control, loss of GABAergic or glycinergic interneurons through cell death, reduced GABA or GABA-synthesizing enzyme (e.g.…”

Section: Pain Mechanisms (Table 2)mentioning

confidence: 99%

“…Mechanisms of disinhibition include reduced descending inhibitory control, loss of GABAergic or glycinergic interneurons through cell death, reduced GABA or GABA-synthesizing enzyme (e.g. glutamate decarboxylase), and altered properties of GABA A receptors, glycinergic receptors and cation-chloride cotransporters 69, 92 . Restoring spinal cord inhibition by, for example, suptype-specific GABA receptor agonists, may offer the opportunity to reduce pain without limiting side effects like sedation 162 .…”

Section: Pain Mechanisms (Table 2)mentioning

confidence: 99%

Toward a Mechanism-Based Approach to Pain Diagnosis

Vardeh

Mannion

Woolf

2016

The Journal of Pain

248

166

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The last few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, both in normal states where it helps protect from injury, and in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. While the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. Here we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision-medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of three steps: pain state, pain mechanism and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as one of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is both consistent with and an extension of the AAPT.

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Spinal presynaptic inhibition in pain control

Cited by 87 publications

References 125 publications

Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice

Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

Toward a Mechanism-Based Approach to Pain Diagnosis

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