Causes Of Potentiation And Transition From Acute To Chronic Pain

The posterior column of the spinal cord can be regarded as a gate, through which nociceptive afferents must travel, in order to reach higher supraspinal pain-processing centers in the CNS. However, it is also the gate, where modulation of pain impulses takes place, resulting in either in diminution or fortification. Also, it is a commonly accepted belief, that opioid receptors and their endogenous ligands, endorphins or enkephalins, play a critical part in the reduction of incoming pain impulses [66, 67, 68]. In particular pro-nociceptive transmitters are of importance, as they cause a fortification of arriving nociceptive afferences [65]. The principle pronociceptive mediators are related to the group of excitatory amino acids, comprising of glutamate, aspartate and the tachykinin group. The latter consists of substance P, the endogenous ligand for the NK1-receptor, as well as neurokinin A, B and C, which bind to the NK2-, NK3- and NK4-receptor respectively. Thus, besides initial nociceptive-related electrophysiological and hormonal changes, sensitivity of peripheral and central nociceptors increases [69, 70], resulting in the initiation of a chronic pain process (Table I-3). Because long-term nociception results in a facilitation of afferent pain afferents [71], they eventually induce morphological changes in the sense of a prevailing condition, a change within the matrix of spinal cord [6,7,72].

All C-fiber-related nociceptive afferents first bind to the excitatory tachykinin receptors. Via this receptor the intracellular G-protein is activated, which can be considered as the main intracellular, "second messenger". It is the G-protein, which converts into adenylcyclase (AC), and the activation of adenosinetriphos-phate (ATP) into cyclic amino monophosphate (c-AMP). This activation results in the formation of several c-AMP-dependant kinases, especially protein kinase A (PKA) and protein kinase C (PKC), resulting in phosphorylation and opening of voltage-dependent Ca2+-ion channels. The increased shift of Ca2+-ions from the extra - to the intracellular space results in an increased excitability of the neuronal cell (Figure I-40). Repetitive long-term activation, however, in particular

Table I-3. Time-dependent levels in the development of chronic pain

First level:

transient stimulus-induced pain

Second level:

tissue damage

Third level:

injury of primary afferent neuron

Fourth level:

injury of central neuron

Fifth level:

activation and sensitization of nociceptors and central pain

pathways with

- disinhibition,

- ectopic activity

- structural reorganization

- phenotype switch (AB- via NGF — > C-fiber)

- sympathetic sprouting

- central sensitization

Sympathetic Sprouting

Figure I-39. Substance P binds to the NKrreceptor, which via PKC (protein kinase C) activation increases Ca2+--transfer through the N-methyl-D-asparate (NMDA) receptor channel, ensuing in the transition of acute to chronic pain through increase through activation of second messenger systems [73]


Activation of PLC, PLA2, PKC, AC NOS cFos

Figure I-40. Summary of events following peripheral injury resulting in activation of neurokinin-and AMPA-receptors, which after Mg+-displacement leads to sensitization of the NMDA-receptor. This is followed by an increase of intracellular Ca2+-transfer. The latter activates several intracellular biochemical mechanisms resulting in the initiation of chronic pain (NK-Neurokinin; AMPA = a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; PKC = Proteinkinase; PLA2 = Phospholipase A2; NMDA = N-methyl-D-aspartate; PLC = Phospholipase C; NOS = Nitric oxide synthetase; c-fos = target gene)

the activation of glutaminergic synapses of the spinal neurons, results in potenti-ation of the NMDA-(N-methyl-D-aspartate)-receptor (Figure I-39), participating in the transmission of nociceptive afferents [73, 74].

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