Descending modulatory pathways arise from many centres in the brain including the thalamus, nucleus raphe magnus and the periaqueductal grey matter (an important site of opioid receptors). They descend via the dorsolateral funiculus of the spinal cord and make presynaptic connections at the first central synapse or with inhibitory interneurones. Transmitters released presynaptically generally act via specific receptors to inhibit nociception (ie reducing pain transmission) by reducing the release of excitatory transmitters by the primary afferent neurones in lamina II. Such receptors include endogenous opioids (endorphins, acting on mu receptors), noradrenaline (acting on alpha-2 receptors) and serotonin (acting on 5-HT receptors). Activation of inhibitory GABA-ergic interneurones (GABAA) and glycine interneurones also decreases nociceptive transmission.
In certain circumstances descending systems also may facilitate nociception, for example following subacute or chronic opioid exposure, thus contributing to hyperalgesia and analgesic tolerance.
The identification of pathways involved with descending modulation of nociceptive input and responses, as well as local regulatory systems, has opened up many possibilities for pharmacological intervention. Descending pathways have been identified which act at a presynaptic level in the dorsal horn. The administration of opioids, notably morphine, into the spinal canal (either by the epidural or intrathecal route) has enabled high analgesic efficacy to be achieved with a lowering of central adverse effects. In addition, the nonopioid presynaptic inhibitory mechanisms explain the use of drugs affecting serotonin (eg tramadol and some antidepressants) and noradrenaline (eg clonidine, tramadol, some antidepressants) in decreasing nociceptive transmission in the spinal cord.
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