Descending modulatory neural pathways function to reduce pain perception and efferent responses by inhibiting pain transmission in the dorsal horn, Periaqueductal gray (PAG), and brainstem rostral ventral medulla (RVM), and other regions of the CNS. The cerebral cortex, hypothalamus, thalamus, PAG, nucleus raphe magnus (NRM), and locus coeruleus (LC) all send descending axons that synapse with, and modulate pain transmission in, noxious cells located in the brainstem and spinal cord dorsal horn. Components of the descending system that play critical roles in modulating pain transmission include the previously mentioned endogenous opioid system, the descending noradrenergic system, and serotonergic neurons (Vanegas and Schaible 2004).
The PAG is an enkephalinergic brainstem nucleus responsible for both morphine-produced and stimulation-produced analgesias. Descending axons from the PAG project to nuclei in the reticular formation of the medulla, including NRM, and then descend to dorsal horn where they synapse with and inhibit wide dynamic range (WDR) and nervous system (NS) neurons. Axon terminals from NRM project to dorsal horn, where they release serotonin and norepinephrine (NE). Stimulation of the RVM activates the serotonergic system descending to the spinal dorsal horn resulting in analgesia. Although serotonin plays an important role in pain, the multiple subtypes of these receptors have confounded development of analgesics acting via these receptors. Axons descending from LC modulate nociceptive transmission in dorsal horn primarily via release of NE and activation of postsynaptic alpha 2-adrenergic receptors. The role of NE in this pathway explains the analgesic effects of tricyclic antidepressants and clonidine. GABAergic and enkephalinergic interneurons in the dorsal horn also provide local suppression of pain transmission. Descending inhibition is enhanced during periods of inflammation because of an overall increased descending inhibitory flow and increased sensitivity of neurons to descending noradrenergic and opioid-mediated inhibition. Unlike the other senses, pain has important subjective and emotional components. Outflow of descending inhibitory impulses from frontal cortex, cingulate gyrus, and hypothalamus contribute are influenced by the patient's psychological and emotional state. Anxiety, psychological stressors, and depression can reduce descending inhibition, thereby lowering the threshold for central sensitization and increasing pain intensity scores. Conversely, psychological support, including imagery, biofeedback, and music therapy can reduce pain intensity by either facilitating descending pathways or inhibiting cortical perception. This may explain the beneficial role of cognitive therapies, which marshal descending inhibitory mechanisms to reduce long-term synaptic strength in acute and persistent pain states.
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