Pharmacologie du récepteur NMDA

Since their discovery in 1987, modulation of N-Methyl-D-Aspartate (NMDA) channels represents an opportunity in the fields of anaesthesia, analgesia and brain protection. The NMDA receptor is one of the sites of connection of glutamate. Glutamatergic receptors are present on almost all the cells of the central nervous system, particularly the structures implied in nociception and memorizing. Glutamate is implied in neuronal growth, mnemonic processes, transmission of painful messages, synaptic plasticity and probably the development of the thought. The complex activation of NMDA receptors implies several types of agonists interacting in co-operation and the simultaneous presence of a strong membrane depolarization. These mechanisms control the intraneuronal entry of calcium, the starting point of the synthesis of second and third messengers, prostaglandins and nitric oxide (NO). NO has the property to retrodiffuse towards the presynaptic element, probably one of the central mechanisms of long term potentiation (LTP). Tolerance and hyperalgesia after administration of opioids, chronic pain, and probably a number of acute and chronic cerebral aggressions share the common calcium entry in the nervous cell through the activation of NMDA receptors. The concept of "use dependence" or "open channel blockade" is a fundamental property of ketamine and related molecules. They bind to an intracanalar site which partially covers the site of fixing with magnesium. Activation of the μ receptors by opioids causes the phosphorylation of NMDA receptors, leading to postoperative tolerance and hyperalgesia. Ketamine is able to prevent hyperalgesia and tolerance by blocking NMDA channels at "anti-hyperalgesic" concentrations. The significant calcic conductance of NMDA receptors makes them the privileged actor of excitotoxicity, an uncontrolled increase in the intraneuronal calcic concentration implied in the pathogenesis of the diseases of Huntington, Alzheimer or Parkinson. NMDA receptors are probably also implied in the pathophysiology of the so-called near-death experiences (NDE).