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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) and 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.

  • 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 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 in an area extending beyond a tissue injury exhibit decreased thresholds for activation. Sensitization can 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 nociceptive pathways. Numerous mechanisms have been implicated in central sensitization, including plasticity mediated by NMDA glutamate receptors.

  • Opiate drugs selectively suppress nociception, but not other sensory modalities, by binding to endogenous opioid receptors in 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 opiates, 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 inhibit certain 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 11–1. When it becomes chronic, however, pain loses its adaptive role as a defender of the body’s tissues and instead ...

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