Many known drugs used to alleviate pain also modulate the activities of enzymes involved in inflammatory processes in peripheral tissues. However, some of the most efficacious analgesics known, including morphine and related compounds, interact with the opioid family of GPCRs within the CNS. The quest for analgesics as efficacious as morphine that lack side effects such as tolerance, addiction, and respiratory depression continues even today, 200 years after the purification of morphine from opium.
Development of better analgesics requires understanding the complexity of the CNS components involved in what we perceive as pain under different conditions. Specialized nerve endings respond to various noxious stimuli in a process known as nociception. Through multisynaptic pathways, these primary afferent nociceptors send information to the dorsal horn of the spinal cord and on to the thalamus and somatosensory cortex. However, not all nociceptive responses are perceived as pain. Perception of pain is modified by emotional states including stress and other inputs. This modulation is thought to occur under various conditions via multisynaptic descending modulatory circuits linking limbic brain regions such as the amygdala to the dorsal horn of the spinal cord.152
Different modalities such as acute and chronic pain may respond to modulation at different points in these pathways. Opioid receptors are expressed in the ascending nociceptive pathways including the dorsal horn of the spinal cord, thalamus, and cortex as well as in the descending antinociceptive pathways. Complex interactions of opioid receptor activation at the different levels of these pathways may explain the remaining challenges to perfecting opioid-based therapies.
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