Neurophysiological Changes Taking Effect During Evolution Of Pain

The skin is the site where approximately 90% of over 3 million nociceptors are located. The peripheral tissue damage, in order to develop into pain of chronic nature, peripheral nociceptors of the skin are irritated over a long period of time. In order to be transmitted, a certain threshold level has to be surpassed, before so called multimodal "wide-dynamic-range" (WDR)-receptors pick up tactile sensation like pressure, heat, distension, and pain is transmitted to the spinal cord. There, aside from inhibitory transmitters such as endorphins, so-called pro-nociceptive transmitters such as substance P, neurokinin A and B, glycine, and glutamate are being released. As in higher central nervous system structures, synaptic potentials activate glutamate receptor (NMDA-receptor, AMPA-receptor), with the consequence that repetitive irritation results in a learning process at the level of the nerve cell. This is because repetitive impulses result in facilitation with spontaneous electrical discharge of action potentials (wind-up-phenomenon), accounting for the increase in output.

Such long-term increase in activity will cause the cell to react to a given stimulus at a higher rate in the near future. This is because nociceptive transmitters act on postsynaptic neurons, resulting in an increased inflow of Ca2+-ions into the cell with the consequence of initiating a deleterious cascade: following opening of the voltage-gated ion channel the increase in Ca2+-ions induce activation of so-called "second messenger" within of the nerve cell. Calcium ions therefore can be considered as important messengers, which guide a series of cell functions, responsible for central sensitization. Via activation of phosphorylation, transcription factors like CREB (c-AMP responsive element binding protein) are initiated, which govern activation of genes and the phenotype formation of nociceptive posterior column cells. In addition, transcription factors will induce specific amino acids to form "immediate-early-genes", necessary to transmit their genetic information into structural information of genes. As a result c-fos and c-jun are synthesized which induce the synthesis of amino acids necessary for the formation of new receptor sites. The consequence of additional binding sites is linked to the process of central sensitization. Since adding new binding sites for transmitters, which are released as the consequence of a nociceptive input, amplification of excitation is initiated with an increase of impulse transduction (Figure I-41). Thus, the neuronal cell being equipped with additional receptors, is put into a permanent state of "attention" (= phase of sensitization and hyperactivity), where neurotransmitters and neurohormones are released spontaneously. Despite a low but constant impulse from the periphery, previously inactive synapses are now being recruited so that the signal information now is transmitted faster and to a higher extent to other spinal cord neuronal cells.

Figure I-41. Following peripheral nerve injury of C-fibers with atrophy there is collateral sprouting into the dorsal root ganglia (DRG), Also, terminal sprouting in the dorsal horn, as well as phenotype switch of AB-fibers to C-fibers is postulated, all of which results in the transition from acute to chromic pain

Figure I-41. Following peripheral nerve injury of C-fibers with atrophy there is collateral sprouting into the dorsal root ganglia (DRG), Also, terminal sprouting in the dorsal horn, as well as phenotype switch of AB-fibers to C-fibers is postulated, all of which results in the transition from acute to chromic pain

In addition nociceptive afferents are functionally interconnected with low-threshold mechano- and thermo-receptors. As a result, there is an expansion of sensitive zones into previous insensitive areas of the skin, and light impulses such as touch, which originate far away from the area of destruction, become painful (development of allodynia). At the final stage, the nervous cell is unable to forget the painful information and a chronic hyperexcitatory state is the consequence. This leads to a long lasting recollection of pain, which is even active when the original trigger stimulus for pain no longer is in existence (Figure I-42). Henceforth, all impulses originally referred to as harmless (e.g. temperature or pressure changes) are now being sensed as painful (= phase of chronic hyperexcitability).

At this moment, opioids such as morphine [30], but also 5-HT2, and 5-HT3-receptor antagonists [75], as well as peptidase inhibitors, that potentiate the action of endorphins by means of an inhibition of enzymatic degradation [76], come into play. These agents are able to prevent the formation of specific amino acids ("immediate-early-genes") and their subfamilies c-jun and c-fos, which usually would result in the formation of additional excitatory receptors. During chronic nociceptive irritation

L-Glutamate

Substance P l

Extreme, long duration of pain e.g. . GABA I Opioid peptide e.g. . GABA I Opioid peptide

Interneuron ^ ^fy fp^ Apoptosis

Necrosis

Figure I-42. Long term and excessive release of excitatory transmitters, due to apoptotic degeneration and necrosis of inhibitory interspinal cells, clinically results in opioid non-responders at the spinal level such increase in the expression of c-fos experimentally could be blocked by morphine, and equianalgesic doses of the K-ligand U50,488H [77]. Such data can be transmitted into the clinic, suggesting that diverse visceral, nociceptive afferences can be blocked adequately by opioids with different receptor affinity. On the other hand antidepressants and anticonvulsants also mediate an antinoci-ceptive effect in humans. The principal mode of antidepressants is activation of the descending inhibitory tract, while anticonvulsants (e.g. carbamazepine, valproate acid, lamotrigine, gabapentin) have a GABAnergic effect. By reducing excessive Ca2+ inflow, programmed cell death (apoptosis) of inhibitory interneurons, which normally release -y-amino butyric acid (GABA) as a transmitter, is prevented. And because the usual loss of GABAnergic inhibition results in intense hyperalgesia and allodynia as well as spontaneous pain arising in the spinal cord level, consequences of an insufficient pain therapy have to be avoided. If such a loss is apparent, it however, can be balanced by compensatory activation of receptors interacting with anticonvulsants and/or benzodiazepines. This is why such "non-analgesic agents" are capable of initiating an analgesic effect. Such compensatory mechanism has been demonstrated in spinal as well as supraspinal areas, where the use of antiepileptic agents resulted in an increase in -y-aminobutyric acid (GABA) [78, 79], deleting the "memory of pain", an effect which clinically goes with a fading of pain sensations.

Such clinical as well as preclinical results indicate that aside from the inhibitory opioids, the GABAnergic system plays an important part in pain therapy at the spinal cord level [80, 81, 82]. This may also explain why baclofen has antinociceptive effects, because it is the prototype GABAB-receptor ligand and muscinol, being the prototype GABAA-receptor subtype ligand. Both GABA-agonists decrease the biochemical cascade within the posterior column of the spinal cord, which follows somatic or visceral nociceptive input, thus avoiding sensitization [83]. Besides direct activation of the GABAa-receptor, also the enzyme glutamatdecarboxylase (GAD),

Figure I-43. Schematic representation of some of the putative neurotransmitters involved in spinal cord stimulation with orthodromically electrical impulses resulting in the release of GABA, which in return decreases excitatory amino acids (EAA = glutamate and aspartate). Also, SCS activates enkephalin (ENK) interneurons, and induces the release of norepinephrine (NOR) and serotonin (5-HT) from descending fibers Adapted from [85]

Figure I-43. Schematic representation of some of the putative neurotransmitters involved in spinal cord stimulation with orthodromically electrical impulses resulting in the release of GABA, which in return decreases excitatory amino acids (EAA = glutamate and aspartate). Also, SCS activates enkephalin (ENK) interneurons, and induces the release of norepinephrine (NOR) and serotonin (5-HT) from descending fibers Adapted from [85]

necessary for the synthesis of GABA, is another potential analgesic agent [78]. In addition, this is how the analgesic effect of a benzodiazepine such as midazolam is being mediated, resulting in an antinociception via the GABAa-receptor [84]. Such results are conclusive in that the GABAnergic inhibitory interneurons in the spinal cord play an significant part in the process of antinociception. They also seem to be the result of spinal cord stimulation, where electrical stimuli induce a release of the inhibitory transmitter GABA (Figure I-43).

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