Bdnf

Nav1.3

Spinal cord

Central terminal primary afferent fiber

Central terminal primary afferent fiber

Post synaptic neuron

Descending systems or interneurons

GLU CGRP NE 5HT GABA ENK ACh

Post synaptic neuron

Figure 3 Pain transmission sites can be simply divided into two: the peripheral compartment (e.g., skin, muscle, organs) that encompasses primary afferent fibers and dorsal root ganglions and the central compartment that includes the spinal cord and brain. A multitude of receptors, transmitters, second messenger systems, transcription factors, and other signaling molecules located all along pain transmission pathways are now appreciated to be involved in pain signaling. Tissue injury results in the release of pronociceptive mediators that activate and sensitize peripheral nerve terminals (peripheral sensitization) through various receptors/channels, leading to phenotypic alterations of sensory neurons with changes of receptor expression in DRG cell bodies and changes in neurotransmitter contents and increased excitability of spinal cord dorsal horn neurons (central sensitization) due to a variety of changes in receptor expression patterns and neurotransmitter release. In addition, interneurons and descending supraspinal systems modulate nociceptive responses either through excitatory or inhibitory effects. 5HT (serotonin), A1 (adenosine 1), a2 (alpha 2 adrenergic), ACH (acetylcholine), ASICs (acid sensing ion channels), BDNF (brain derived nerve growth factor), CCKB (cholecystokinin), CGRP (calcitonin gene related peptide), ENK (enkephalines), GABA, GAL (galanin), GLU (glutamate), mGlu (metabotropic glutamate receptors), Nav1.3 (sodium channels), Nav1.8 (sodium channels), NE (norepinephrine), NK-1 (neurokinin-1 receptor), NMDA (N-methyl-D-aspartate receptor), NPY (neuropeptide Y), opioid, P2X3 (ATP receptor), SP (substance P), TRP (transient receptor potential), and TRPV1 (vanilloid receptor 1).

field of spinal neurons. In addition, it reflects a complex series of changes occurring in the spinal cord that may promote long-lasting increases in dorsal horn neuron excitability. This process is also know as 'wind-up' in that the response of sensitized dorsal horn neurons is exaggerated relative to the normal situation.20-22 While both peripheral and central sensitization play a role in nociceptive chronic pain, central sensitization clearly plays a key role in neuropathic pain. Thus, central sensitization also explains the observation that established pain is more difficult to suppress than acute pain because of the maladaptive changes that have taken place in the CNS. Interestingly, not only neurons, but also glia, e.g. astrocytes and microglia, as well as infiltrating mast cells are involved in the generation and maintenance of central sensitization.23'24

In addition to the activation of pronociceptive inflammatory and/or neurotrophic messengers noted above, the sensitization of the nervous system in response to chronic pain involves the alteration and/or activation of many neurotransmitter systems that have been extensively reviewed elsewhere.6,15 Chronic pain is mediated by altered neuronal excitability involving activation of sodium and calcium channels in both peripheral and spinal neurons. Additionally, there is enhanced glutamatergic activity and a concomitant decrease in GABAergic inhibitory neuromodulation at the level of the dorsal spinal horn.6,15 This altered neurochemical profile contributes to the heightened state of neuronal excitability (e.g., wind-up) and can be viewed as a shift in the balance of excitatory and inhibitory systems that also incorporates activation of intracellular signaling cascades (e.g., ras-mitogen-activated protein kinase (MAPK) pathway) and recruitment of neurotrophic neuropeptides including substance P, neuropeptide Y, and brain-derived neurotrophic factor (BDNF). These changes in spinal neuron neurochemistry are also accompanied by upregulation of specific excitatory amino acid receptors (e.g., a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA)), as well as increased calcium and potassium ion channel activity. Taken together, chronic pain is associated with a large variety of deranged patterns of neurotransmission at multiple levels of the neuroaxis with considerable target and pathway redundancy. Thus, in the absence of ongoing injury, chronic pain can be viewed as a disease in itself. The enhanced appreciation of the many neurochemical and neurophysiological alterations in neuronal function associated with chronic pain has led to the development of both new preclinical models of pain and a variety of potentially useful therapeutic interventions.

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