Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception

Persistent postsurgical pain, a pain syndrome that can develop after surgery, is a significant public health problem. Approximately 50 % of surgical patients suffer from persistent pain after surgery, of whom at least 5–10 % have severe pain [1]. The condition affects their quality of life and has important legal and medico-economic ramifications. Pharmacological management of persistent surgical pain conditions are dominated by two classes of medications: opioids and nonsteroidal anti-inflammatory drugs. Many of these painkillers have limited effectiveness or serious side effects, such as nausea/emesis, constipation, tolerance or hyperalgesia [1‐4]. Understanding the factors that may cause and/or affect the development and maintenance of persistent surgical pain may provide insight into novel prevention or treatment strategies.

Although many forms of injury and stress occur spontaneously, patients know the precise timing of the elective surgical insult and ensuing pain in advance. In addition to surgical factors, psychosocial, socio-environmental, and patient-related factors appear to modulate risk of developing persistent postsurgical pain. Several psychosocial risk factors have been identified, including anxiety, depression, pain catastrophizing, and fear of surgery [4]. Self-reported sleep disturbance-induced stress before and after surgery also constitutes the strongest determinant of postsurgical pain [5].

Substantial evidence from clinical observations has demonstrated that sleep deprivation-caused chronic stress increased basal pain perception in healthy subjects [6, 7]. Some surgical patients with chronic severe physical or psychological stress self-reported increased basal pain sensitivity or exacerbated existing pathological pain before surgery [8, 9]. In preclinical studies, chronic stress induced by immobilization exacerbates mechanical allodynia after peripheral nerve injury [10]. Sleep disturbance-induced chronic stress leads to thermal hyperalgesia and an increased response to electrical stimulation in intact, experimental animals [6, 11‐13]. Nevertheless, most surgical patients have normal pain perception before surgery although they have stress caused by risk factors such as depression, anxiety, fear of pain and surgery, and/or sleep disturbance for several days before and/or after surgery [4, 5]. Our recent findings suggest that pre- and post-surgical short-term sleep disturbance did not affect basal pain perception but did delay postsurgical pain recovery [14]. Whether or not short-term stress caused by other risk factors affects the recovery from postoperative pain is still elusive.

To model short-term stress caused by depression, the present study utilized two preclinical animal models of stress—immobilization stress and forced swimming stress [15‐17]—to determine the optimal duration of immobilization or forced swimming that did not alter basal paw withdrawal responses to thermal, cold, and mechanical stimuli. We then determined whether the short-term immobilization or forced swimming under optimal conditions enhanced the magnitude and/or duration of thermal, cold, or mechanical hypersensitivity induced by a hind paw incision. Finally, we examined whether this short-term immobilization or forced swim produced other physiological or behavioral signs of stress.

Surgery-induced persistent pain is a common clinical symptom. Identifying risk factors that exacerbate post-surgical pain during the perioperative period may help us to predict which patients may experience delayed recovery and offer an opportunity to manage post-surgical pain effectively. Chronic stress increased basal pain perception and worsen existing pathological pain [8, 9]. However, most surgical patients have normal physiological, psychological health status and normal pain perception before surgery although they have to some extent stress during pre- and/or post-operative period. Whether this short-term stress affects persistent post-surgical pain is still elusive. We recently reported that pre- and post-surgical short-term sleep disturbance did not affect basal pain perception but did delay postsurgical pain recovery [14]. Here, we report that pre- or post-surgical exposure to short-term stress prolongs the duration of incision-induced mechanical, thermal, or cold hypersensitivities even if it does not alter basal nociception. Our findings suggest that prevention of short-term stress during pre- and post-operative period may help the patients recover from postoperative pain.

Immobilization and forced swimming are established stressors in rodents as defined by their effectiveness to activate the hypothalamic–pituitary–adrenal (HPA) axis and produce behavioral signs of depression [15‐17]. We established two regimens of immobilization and forced swimming that did not alter basal responses to mechanical, thermal, and cold stimuli in naïve rats. These exposures to immobilization and forced swimming may model clinical conditions in most patients that have normal pain perception before surgery, although they may experience transient HPA axis activation in association with short-term fear of pain, anxiety, depression, and pain catastrophizing during pre- and post-operative periods. Evidence of stress in our current models is demonstrated by increased immobility time in a forced swim test, decreased preference for sucrose, and elevated serum CORT levels. Interestingly, short-term immobilization or forced swimming stress either before or after surgery prolonged post-surgical pain, although it did not alter the magnitude of incision-induced hypersensitivity to mechanical, thermal, or cold stimuli. Blocking spinal glucocorticoid receptor or removing the adrenal glands (that are the primary source of CORT) completely abolished the prolongation of incision-induced hypersensitivity after immobilization stress. Given that glucocorticoid receptor is expressed predominantly in the neurons of spinal cord and dorsal root ganglion [25‐27], these results indicate that CORT-triggered activation of glucocorticoid receptors in spinal cord and dorsal root ganglion (rather than in brain) neurons may mediate this prolongation. Intrathecal exogenous CORT would be expected to delay the recovery of surgical pain. This expectation is strongly supported by a previous study showing that systemic exogenous administration of CORT reduced the pain threshold in the ipsilateral hind paw after peripheral nerve injury [10]. It should be noted that the ADX cannot rule out the involvement of other hormones (e.g., catecholamines) in short-term stress-induced prolongation of post-surgical pain as both adrenal cortex and medulla are removed. Unexpectedly, both male and female rats exhibited similar magnitudes and durations of postsurgical pain in either presence or absence of immobilization stress in our observations. Sex differences in response to pain and stress have been reported [21, 22]. No sex difference in our observation may be related to the short-term immobilization stress and no gender distinct in incisional pain [28].

The distinct mechanisms affected by short-term stress that do not alter basal pain perception but do prolong incision-induced hypersensitivity are unknown, but may involve one or more of the following signaling molecules and processes. Nitric oxide synthase-containing magnocellular neurons of the rat hypothalamus, which contribute to the descending projection to the spinal cord, express Fos following stress [29]. Repeated stress reduces ADP hydrolysis [30], increases 5′-nucleotidase activity [30], and produces apoptosis [31] in the spinal cord. More interestingly, immobilization stress not only exacerbates nerve injury-induced mechanical allodynia but also enhances nerve injury-induced expression of extracellular signal-regulated kinase phosphorylation in the superficial dorsal horn of spinal cord [10]. Blocking spinal cord NMDA receptor prevents stress-induced exacerbation of allodynia after spared nerve injury [10]. It was reported that spinal cord NMDA receptor is not involved in central mechanisms underlying postoperative pain in non-stressed animals [32, 33]. Whether the role of NMDA receptors and the signaling components described above participate in the short-term stress-induced prolongation of incisional pain in the present study remains to be further defined. Not without saying, other potential mechanisms cannot be ruled out.

In conclusion, the present study showed that short-term stress does not affect basal nociception but does prolong post-surgical hypersensitivity to mechanical, cold, and thermal stimuli applied to the incision site. Although the detailed mechanisms underlying this effects are still unclear, our findings indicate that prevention of short-term CORT signaling during pre and post-operative periods may facilitate recovery from postoperative pain for patients.