Nozizeption, Schmerz und Antinozizeption: neurobiologische Aspekte

Zusammenfassung

Die Physiologie der Schmerzwahrnehmung beruht auf einer komplexen Interaktion peripherer, spinaler und supraspinaler Strukturen des Zentralnervensystems (ZNS). Auf jeder Ebene des ZNS erfolgt eine Modulation nozizeptiver Information, wobei die zwei wichtigsten Transmittersysteme der Nozizeption und der Antinozizeption, das N-methyl-D-aspartate (NMDA)- und das Opioid-Rezeptor-System, eine nahezu identische Verteilung zeigen. Glutamat, der natürliche exzitatorische Transmitter aller Neurone mit ionotropen und metabotropen NMDA-Rezeptoren, bewirkt durch Öffnen des Ionenkanals für Ca²⁺ und die dadurch ausgelöste Aktivierung der intraneuronalen Stickoxidsynthase (NOS) die Freisetzung von Stickoxid (NO). Diffusion des NO zu Nachbarneuronen erhöht deren cGMP-Synthese und Aktivität, die vor allem auf spinaler Ebene zur Hyperalgesie oder Allodynie führen kann, wenn über diesen Mechanismus Transmitter aus Endigungen nozizeptiver Neurone freigesetzt werden. Die periphere Sensibilisierung nozizeptiver Axone erfolgt meist über Serotonin, Bradykinin oder Prostaglandine. Während die μ- und δ-Opioid Rezeptoren die NMDA-Rezeptor vermittelte Nozizeption hemmen oder verstärken, wirken κ-Opioide durch direkte Interaktion mit dem NMDA-Rezeptor auf diesen blockierend. Unter Stress freigesetztes Corticotropin-releasing Hormon (CRH) wirkt auf allen Ebenen des ZNS antinozizeptiv.

Abstract

The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca²⁺ which stimulates nitric oxide synthase (NOS) and, hence, the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighbouring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, µ- and δ-receptors either inhibit or potentiate NMDA receptor-mediated events, while κ opioids antagonize NMDA receptor-mediated activity. Recently, stress-induced release of CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive, and locomotor components.

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