DURING the last 3 decades, it has been widely reported that intense fear and stress suppress pain. In animals and humans, the typical effect of many stressors was reported as stress-induced analgesia (SIA).1However, stress was also reported to exacerbate chronic widespread pain syndromes (e.g ., in patients with fibromyalgia).2In animals, repeated exposure to stressors (e.g ., swim stress, restraint, and social defeat) were shown to produce hyperalgesia.3If the mechanisms of SIA have been widely described, those underlying stress-induced hyperalgesia (SIH) remain poorly understood.

In the current issue of Anesthesiology, Donello et al .4report that adrenoceptor-mediated sympathetic efferent mechanisms contribute to SIH. These data bring novel information regarding the effects of psychologic factors in preclinical pain modeling.

Hyperalgesia can be associated with potentiated adrenergic sensitivity of primary afferent fibers as a result of up-regulation of α2-adrenergic receptors and exacerbation of neurogenic inflammation by α1-adrenergic receptors.

Donello et al .4enhance our understanding of the sympathetic nervous system and hyperalgesia. They report norepinephrine exacerbated nociception after stress. They also describe how sympathetic postganglionic nerves can facilitate pain hypersensitivity via  an α1adrenoceptor mechanism even when sympathetic outflow is uninhibited. By using α2A-adrenergic receptor knockout mice or by administering an α2receptor antagonist, they showed feedback inhibition of norepinephrine release at α2receptors is likely reduced by stress. This could result in a deregulation and enhanced norepinephrine release from sympathetic postganglionic nerves and significant sensitization of sensory afferents to SIH (see fig. 8 of Donello et al .4).

Other studies indicate other mechanisms may contribute to SIH. For example, epinephrine has been implicated as a factor in SIH. Khasar et al . hypothesized changes in β2-adrenergic receptor signaling and prolonged elevation of circulating epinephrine were responsible for the induction and maintenance of mechanical SIH.5In addition, the involvement of descending nociceptive pathways in SIH has been described recently in a rat model of social defeat-induced hyperalgesia.6However, there are limitations to these basic science studies. These preclinical experiments of SIH were performed in animals without any history of pain or opioid use before stress exposure, factors that are common in patients in our daily practice. There is some evidence that endogenous opioid systems paradoxically may trigger SIH. For example, when SIA was observed in naïve rats, 1-h stress exposure induced SIH for several hours in animals with a previous history of nociception and opioid exposure. Such pain nociceptive susceptibility after injury, pain, opioid use, and stress could contribute to central nervous system sensitization and perhaps the development of chronic pain.7 

In our daily clinical practice, most patients present with a history of chronic pain, and some have a history of chronic opioid use and often associated anxiety and depressive disorders. Depression in chronic pain is an important psychologic parameter in patients requiring pain treatment. Chronic pain and depression are present together in patients, and negative mood can be responsible for worsening pain complaints.8Whether the same ability to transform SIA into SIH persists in such patients remains to be determined.

Surgery induces a high level of stress in patients. Because chronic exposure to stress markedly exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, psychologic factors are associated with acute pain and the persistence of pain after surgery and could facilitate the development of chronic pain.

Developing animal models for SIH4is of considerable interest to the pain field. Donello et al . report that nociception and acute stressors could cause a deregulation of the sympathetic nervous system and might have clinical significance in chronic stress conditions. Indeed, disinhibition of sympathetic nervous system outflow and subsequent SIH could exacerbate pain and facilitate the development of chronic pain. In the specific perioperative context, treatments aimed at modifying the development of SIH for the long term after surgery are of interest. For example, in patients scheduled for surgery, interfering with the mechanisms responsible for the transformation of SIA into SIH could reduce not only acute postoperative pain, but also perhaps the likelihood of developing persistent pain and decrease the magnitude of chronic pain after surgery.9This might be even more appropriate in patients with chronic pain who are scheduled for surgery.

Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, Seattle, Washington. prichebe@u.washington.edu

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