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  • Nociception is the form of somatic sensation that detects noxious, potentially tissue–damaging stimuli. Pain has both a localizing somatic sensory component and an aversive emotional and motivational component.

  • Pain begins with peripheral nociceptors, which have their cell bodies in dorsal root ganglia (DRG) or in the trigeminal ganglia in the head; these neurons synapse, respectively, in the dorsal horn of the spinal cord or the trigeminal nucleus, the medullary extension of the dorsal horn.

  • Itch is transduced by analogous neural circuits as those described for pain.

  • Peripheral nociceptors express a set of channels, most notably transient receptor potential (TRP) channels, that are sensitive to noxious mechanical, thermal, and chemical stimuli. These neurons also express receptors for numerous inflammatory mediators and substances released by damaged cells.

  • Primary nociceptors release a large number of neuropeptide and nonpeptide neurotransmitters in the dorsal horn and trigeminal nucleus. These regions are important sites of integration for both ascending nociceptive information and descending antinociceptive (endogenous analgesic) influences.

  • Sensitization is a clinically significant process in which nociceptors exhibit decreased thresholds for activation. Sensitization can occur in response to injury or be initiated by inflammatory mediators such as prostaglandins and leukotrienes.

  • Damage to neurons in nociceptive pathways can lead to severe chronic pain syndromes, termed neuropathic pain.

  • Plasticity within the dorsal horn and trigeminal nucleus, termed central sensitization, may be key in the initiation of chronic pain syndromes by increasing the excitability of neurons in central nociceptive pathways. Numerous mechanisms have been implicated in central sensitization, including plasticity mediated by NMDA glutamate receptors.

  • Opioid drugs selectively suppress nociception, but not other sensory modalities, by binding to endogenous opioid receptors on peripheral nociceptors and central descending analgesic pathways. They are the most potent analgesic compounds known, but their chronic use is limited by tolerance to their analgesic effects and by risk for addiction.

  • Nonsteroidal anti-inflammatory drugs (NSAIDs), which are more weakly analgesic compared with opioids, act by blocking prostaglandin–mediated sensitization, specifically by inhibiting the enzyme cyclooxygenase that is required for the synthesis of prostaglandins from arachidonic acid.

  • Several other medications are used to treat chronic pain syndromes, including combined serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants and compounds (eg, gabapentin, pregabalin) that bind to accessory subunits of voltage–gated Ca2+ channels.

Chronic pain is a significant public health problem associated with severe patient suffering and disability and, in some cases, drug abuse. Pain begins, however, as an adaptive response to actual or potential harm to the body with the stimulation of peripheral nociceptors, neurons specialized to detect noxious stimuli. Pain is not simply a modality of somatic sensation such as touch or vibration sense, however. Pain also has physiologic, behavioral, and aversive emotional components. Without its alerting and aversive components, its activation of withdrawal reflexes and avoidance behaviors, or its capacity to inscribe powerful emotional memories, pain would not reliably trigger escape from danger and avoidance of future harm (Box 11-1). When it ...

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