Animal models of chronic pain: Advances and challenges for clinical translation

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Pain is often considered a curse that society is better off without. On the surface, the notion of a pain‐free existence seems ideal, but the ability to sense pain is vital to our survival and is a key component of the body's natural defense. Acute nociceptive pain is a normal function of the nervous system that provides important sensory information about the environment, and it is an early warning mechanism that protects against noxious heat, extreme cold, chemical irritants, and mechanical tissue damage. These noxious stimuli activate peripheral nociceptors, triggering action potentials that propagate into the dorsal horn of the spinal cord, where incoming nociceptive signals are actively processed and filtered before being relayed to the brain. Activation of specific centers within the brain produces a rich tapestry of sensory, emotional, autonomic, and motor responses that collectively shapes our experience and perception of pain.
The importance of perceiving pain is most striking in patients with congenital insensitivity to pain (CIP), a rare genetic disorder linked to altered expression of several genes (Nagasako et al., 2003; Oertel and Lötsch, 2008). In particular, a null mutation in the SCN9A gene encoding for the Nav1.7 sodium channel is causally linked to the inability of CIP patients to feel thermal and mechanical pain (Cox et al., 2006). Without acute nociceptive pain, individuals with CIP may continue to engage in harmful behavior that puts them at risk of severe injuries and even death (Protheroe, 1991). In stark contrast to CIP patients, who feel no pain, chronic pain patients have a heightened sensitivity to pain. Chronic or pathological pain results from abnormal functioning of the nervous system, with pain persisting far beyond the resolution of the injury or insult. The cardinal feature of chronic pain is pain hypersensitivity, which manifests as spontaneous pain (pain in the absence of an overt stimulus), allodynia (pain resulting from an innocuous stimulus), and/or hyperalgesia (an exaggerated pain response to a noxious stimulus). These opposing pain disorders, CIP and chronic pain, illustrate the paradox of pain; although acute pain is necessary and protective, chronic unremitting pain confers no known physiological advantage and can be so severe that individuals sometimes prefer death. Great strides have been made toward understanding the mechanisms of acute pain, yet little is known about the core processes that transform acute pain to chronic pain. A peculiar aspect of pain is the great variability among individuals in the likelihood of transitioning from acute to chronic pain. The location, type, or extent of injury is not necessarily predictive of the severity or chronicity of the ensuing pain. For example, the extent of cartilage degradation is not predictive of pain reported by osteoarthritis patients. It has, however, become apparent that chronic pain is not simply long‐lasting acute pain and that the underlying mechanisms of these two types of pain are fundamentally distinct: acute pain is a physiological function of the normal nervous system, whereas chronic pain is the manifestation of a pathologically altered nervous system (Woolf and Salter, 2000).
Chronic pain affects more than 1.5 billion people worldwide and is a major burden on health care systems, costing over 600 billion dollars annually in the United States alone (Global Industry Analysts Inc., 2011; The National Academies Press; 2011). Chronic pain can be broadly classified into chronic neuropathic pain (arising from nerve injury or disease) and chronic inflammatory pain (pain as a result of persistent or unresolved inflammation).
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