Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity

The pro- and anti-inflammatory properties of the cytokine interleukin-6

Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2003

Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

In this review, we consider the potential functional role of beta-band oscillations, which at present is not yet well understood. We discuss evidence from recent studies on top-down mechanisms involved in cognitive processing, on the motor system and on the pathophysiology of movement disorders that suggest a unifying hypothesis: beta-band activity seems related to the maintenance of the current sensorimotor or cognitive state. We hypothesize that beta oscillations and/or coupling in the beta-band are expressed more strongly if the maintenance of the status quo is intended or predicted, than if a change is expected. Moreover, we suggest that pathological enhancement of beta-band activity is likely to result in an abnormal persistence of the status quo and a deterioration of flexible behavioural and cognitive control.

Beta-band oscillations--signalling the status quo?

The National Academy of Sciences through its Institute of Medicine (IOM) has produced a major scholarly assessment of pain in America. This document is a tremendous contribution to the evolving nec...

Relieving pain in america: a blueprint for transforming prevention, care, education, and research

The invention relates to novel, specifically expressed proteins, nucleic acid sequences, recombinant nucleic acid structures containing said nucleic acid sequences, and vectors containing the aforementioned nucleic acid sequences or recombinant nucleic acid structures, which code for the proteins. The invention also relates to transgenic organisms containing said nucleic acid sequences, said recombinant nucleic acid structures or said vectors, in addition to monoclonal or polyclonal antibodies, which are oriented against the isolated proteins. The invention further relates to a method for finding substances having a specific binding affinity with the inventive proteins, and a method for qualitatively or quantitatively detecting the inventive nucleic acid sequences or the inventive proteins. Also disclosed is the use of said nucleic acid sequences and proteins.

Neuronally expressed protein and use thereof

Chronic neuropathic pain is associated with structural plasticity of the brain on different spatial scales, yet, little is known on the mesoscopic scale of tissue composition. Here, we determined the cellular composition of cortical areas and structural variability of entire neurons during the development of chronic neuropathic pain using longitudinal in vivo two-photon microscopy and behavioral assessment. When monitoring cell type composition in response to spared-nerve injury in 84 cortical volumes containing ∽25000 cells each, we found neuronal loss in the secondary motor cortex region M2 immediately adjacent to the cingulate cortex already one week after surgery. Loss of mostly interneurons was also evident when monitoring individual M2 neurons over time. This neuronal loss was preceded by decreased spine density and loss of distal dendritic branches. In conclusion, our work delineates M2 as a novel site and neuronal loss as a so far underappreciated mechanism underlying chronic neuropathic pain states.

https://www.biorxiv.org/content/biorxiv/early/2023/01/06/2023.01.05.522932.full.pdf

Loss of secondary motor cortex neurons in chronic neuropathic pain

Background Activity-dependent facilitation of pain is functionally linked to plasticity at synapses between peripheral sensory afferents and spinal projection neurons. However, the underlying cellular and molecular mechanisms are not well-understood [1]. We observed that long-term potentiation at these synapses involves a presynaptic mechanism comprising activity-induced decrease in synaptic failures. This process involves activation of the cGMP-dependent protein kinase-I (PKG-I) in presynaptic terminals of nociceptive afferents and potentiation of vesicular transmitter release via modulation of IP3 receptors and myosin light chains. Mice lacking PKG-I specifically in nociceptors did not develop spinal long-term potentiation and showed marked defects in pathological pain in vivo.

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Presynaptic cGMP-dependent protein kinase-I mediates synaptic potentiation in spinal amplification of pain

Abstract Brain circuits involved in pain chronicity shift from areas involved in nociceptive processing to those associated with emotional and motivational processes. They overlap with circuits relevant for anxiety, fear and depression and are characterized by deficient prefrontal control mechanisms. Noninvasive brain stimulation techniques such as repetitive transcranial magnetic stimulation, transcranial direct and alternating current stimulation directly impact on these circuits and pain. Neurofeedback and brain-computer interfaces as well as various types of cognitive and behavioral interventions also alter these circuits. The analysis of brain changes related to pain chronicity helps to mechanistically tailor interventions to patient characteristics, can increase treatment efficacy and efficiency and can identify new treatment approaches.

Brain-based interventions for chronic pain

Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the CNS, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here, we report a novel form of neuroglia signaling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the metabolic signaling molecule PTG exclusively in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviors and promoted faster recovery by shortening pain maintenance. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. Finally, metabolic analysis indicated that glycolysis and lactate transfer between astrocytes and neurons fuels spinal neuron hyperexcitability. Spinal glycogen-metabolic cascades therefore hold therapeutic potential to alleviate pathological pain.

Rohini Kuner

Papers

Neuronally expressed protein and use thereof

Loss of secondary motor cortex neurons in chronic neuropathic pain

Presynaptic cGMP-dependent protein kinase-I mediates synaptic potentiation in spinal amplification of pain

Brain-based interventions for chronic pain

Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of persistent pain