La complexité des aspects physiopharmacologiques de la douleur

Résumé

Le message nociceptif périphérique est véhiculé par différentes fibres nerveuses ou nocicepteurs polymodaux, fibres A delta et C de petit calibre, activées par des stimulations mécaniques, thermiques et chimiques.

De nombreuses substances chimiques participent à la genèse des messages nociceptifs (histamine, sérotonine, prostaglandines..). Par ailleurs, des neuropeptides, comme le peptide lié au gène de la calcitonine (CGRP) et surtout la substance P, ont vu leur rôle clairement démontré dans 1’activation de l’inflammation neurogène précoce. D’autres substances (bradykinine, cytokines…) sont impliquées dans la persistance du processus douloureux, ainsi que le facteur de croissance neuronale (NGF), qui accroît l’excitabilité cellulaire des nocicepteurs et favorise l’action du système sympathique qui joue un rôle majeur dans le contrôle de la douleur.

Du fait de la diversité de ces substances interagissant toutes entre elles, l’approche pharmacothérapeutique est extrêmement complexe. Cependant, de nouvelles voies thérapeutiques offrent des perspectives intéressantes, notamment la recherche d’inhibiteurs spécifiques de la cyclo-oxygénase 2 (COX 2), induite par le processus inflammatoire, et qui respecteraient la COX 1, constitutive et physiologique, offrant ainsi une meilleure tolérance que les AINS actuels qui agissent sur les deux COX.

La synthèse d’antagonistes de la bradykinine, de la substance P et des récepteurs au N-méthyl-D-aspartate (NMDA), constitue un des axes de recherche majeurs pour la mise au point d’analgésiques. La notion de centre unique de la douleur est remise en cause par le fait qu’aux différents niveaux du circuit de la douleur, le transfert de l’information nociceptive est constamment modulé par différents systèmes de contrôles.

Ainsi au niveau segmentaire, 1’activation des fibres cutanées de gros calibre (Aα et β), bloque les stimuli douloureux véhiculés par les fibres de petit calibre. Ce mécanisme de “gate control” de la corne postérieure de la moelle est utilisé en thérapeutique par les techniques de neurostimulation électrique. Les aspects pharmacologiques sont moins bien connus et dépendent pour partie des systèmes Gabaergiques et endomorphiniques.

Les contrôles d’origine supraspinale passent par les voies descendantes inhibitrices et sont très complexes. Ils mettent en jeu les voies bulbo-spinales sérotoninergiques et les voies noradrénergiques dont les effets s’exercent par la stimulation des récepteurs α2-noradrénergiques. La mise en évidence de ces systèmes offre de nouvelles perspectives dans la lutte contre la douleur.

English Abstract

Understanding pain or, more precisely, the different types of pain, is above all a question of understanding its physiological mechanisms and, in this regard, the role of basic research has without doubt been to trigger the development of new therapeutic strategies.

In an approach to these problems, the main international teams involved in pain research have attempted to develop models of experimental pain in rats. Clearly, research aimed at developing these models is controlled by certain ethical considerations; however, in this context, the end must surely justify the means. The main models used (acute or chronic inflammation, rheumatoid arthritis, peripheral neuropathy) certainly do not give a comprehensive representation of all the pain syndromes encountered in clinical practice, but they do provide new data concerning the physiological, behavioural and pharmacological aspects of pain. While giving a brief description of the complexity of the pain circuit, this article also makes reference to certain pharmacological approaches to the treatment of pain.

Peripheral nociceptive messages are conveyed by a mosaic of unmyelinated free fibres distributed throughout cutaneous, muscular and articular tissue, and within the visceral walls. They are then transmitted via various nerve endings (polymodal nociceptors) by small diameter A delta and C fibres, which are activated by mechanical, thermal and chemical stimuli. It is nevertheless difficult to ascertain whether these small diameter fibres are involved only in nociception (specific nociceptors) or whether pain causes an excessive activation of these receptors, which under normal conditions have a role in the reflex that regulates various functions (nonspecific nociceptors).

Numerous chemical substances play a part in generating nociceptive impulses (e.g. histamine, serotonin, prostaglandins). Furthermore, the role of neuropeptides, such as calcitonin gene-related peptide and particularly substance P, has been clearly demonstrated in the activation of early neurogenic inflammation. Other substances, such as bradykinin and cytokines, are involved in prolonging the sensation of pain. Nerve growth factor also prolongs the sensation of pain by increasing the cellular excitability of nociceptors and promoting the action of the sympathetic nervous system, which has a major role in controlling pain.

The very great diversity of all these interacting substances makes the pharmacological treatment of pain extremely complex. Nevertheless, new therapeutic advances are providing interesting approaches, particularly the development of specific inhibitors of cyclo-oxygenase 2 (COX 2), which is produced by the inflammatory process. Such inhibitors would preserve COX 1, which is both constitutive and physiological, and thereby provide improved tolerability compared with currently used NSAIDs, which act upon both COX pathways.

A major focus of research relating to new analgesics is the development of synthetic antagonists of bradykinin, substance P and N-methyl-D-aspartate receptors. An improved understanding of anatomical and electrophysiological processes has led to the discovery of new ascending pathways that transmit nociceptive messages to the reticular formation, the hypothalamus, and the amygdala, as well as to certain areas of the cortex. As a result, the notion of one single pain centre is no longer valid. This idea is further reinforced by the knowledge that, at different stages of the pain pathway, different control systems constantly modulate the transmission of nociceptive information.

Consequently, at a spinal level, activation of the large diameter cutaneous fibres (Aα et β) blocks pain stimuli transmitted by the small diameter fibres. Knowledge of this ‘gate control’ mechanism of the posterior horn of the spinal cord is put to practical application in treatments involving transcutaneous electrical nerve stimulation. Neurotransmitters involved at the spinal level are not so well understood, but rely in part on the GABAminergic and endomorphine systems.

The complex supraspinal control is transmitted via descending pathways, which exert an inhibitory effect. These pathways activate the serotonergic bulbospinal pathways and the noradrenergic pathways, which operate by stimulating the α2 noradrenergic receptors. The discovery of these systems has opened up new perspectives in the fight against pain.

Certain α₂ noradrenergic agonists are capable of producing strong analgesic effects. In addition, it has been shown that endomorphines act not only within the medulla by reducing the transmission of nociceptive messages but also indirectly, by increasing the activity of inhibitory descending systems.

A promising new therapeutic approach might well be concurrent administration of weak doses of morphine with, in order to potentiate its effects, other antagonist or agonist molecules. The combination of morphine and α₂ noradrenergic agonists has already proved effective in animal studies and in a few human examples. The advantage of tramadol is that this single molecule possesses weak opioid activity via μ receptors and a noradrenergic agonist activity via α₂ receptors.