Modeling How Environment, Exercise, and Sleep Affect Pain
Adverse life events, stress, and lack of sleep can increase the intensity of felt pain and diminish the ability of people to function with chronic pain, while interventions that minimize stressors and increase social and physical activities can improve quality of life. The bases for these effects are the subject of much research, but the exact mechanisms are unknown. Studies presented in posters at Neuroscience 2011, the annual meeting of the Society for Neuroscience, held November 12-16, 2011, in Washington, DC, offer a collection of new animal models that promise to help untangle the complex interactions between pain and the social and environmental factors that shape its impact.
Studies on aging and neurodegenerative disease show that a stimulating environment (social interactions, mental activity) and exercise act as neuroprotective forces in animal models and people. Could the same be true in chronic pain after nerve or spinal cord injury? Several posters showed positive effects of environmental enrichment or exercise on neuropathic pain arising from injury in animal models. In addition, new work on models of sleep deprivation shows that even a moderate reduction in sleep affects neuropathic or inflammatory pain behaviors in animals, and that different pain conditions disrupt sleep in distinct ways.
Socializing and exercising
Lucie Low, working in the lab of M. Catherine Bushnell at McGill University, Montreal, Canada, reported that the presence of companions and other distractions could lessen pain behaviors in rats with neuropathic pain due to nerve injury. Rats with spared nerve injury (SNI) were randomly assigned to an enriched environment (a large, multilevel cage housing eight rats with climbing ladders and other toys) or restricted quarters (a normal cage housing one animal). Normally, after SNI, animals show increased mechanical hypersensitivity and decreased exploration behaviors. Low found that, compared to conventionally housed rats, the rats switched to enriched housing had less mechanical hypersensitivity on the ipsilateral paw two or four weeks later. These results agree with previous work in mice using the chronic constriction injury model of neuropathic pain (Abramov et al., 2009). The enriched rats also showed more exploratory and locomotion behaviors. “These effects are similar to the positive effects of psychosocial interventions in humans,” Low said.
Low’s study, in which she switched animals to an enriched environment shortly after nerve injury, modeled a preventive approach. Pascal Vachon of the University of Montreal, St-Hyacinthe, Quebec City, Canada, looked at the effect of environmental enrichment on established pain behaviors. Mice with SNI were kept for three months in regular housing (four to five mice per cage with standard bedding), then randomized to an enriched environment (three mice per cage with an exercise wheel and toys) or to a restricted environment (one mouse per cage). After one or two months in the enriched environment, animals became less sensitive to cold or mechanical pain, whereas the restricted animals became more sensitive. Levels of pain peptides Substance P and calcitonin gene-related peptide (CGRP) were decreased in the spinal cord of enriched animals. Measures of motor skill and anxiety were not changed. The results indicate that an enriched environment can alter chronic pain well after the time of injury, and that a restricted environment can make the pain worse.
In both studies, the animals experienced enhancements in both their social and physical environments, and Low said future work will aim at separating the effects of the two.
Another study reported positive effects of exercise on pain after spinal cord injury. The benefits were associated with elevation of trophic factor levels in the spinal cord. Megan Detloff from Drexel University in Philadelphia, Pennsylvania, looked at levels of glial-derived neurotrophic factor (GDNF) and artemin after spinal cord injury. Both factors support the survival and function of sensory neurons, and boosting spinal GDNF has been shown to reverse allodynia in animal models of neuropathic pain. In Detloff’s spinal cord contusion model, a subset of animals develops neuropathic pain, and has reduced GDNF and artemin in the spinal cord and dorsal root ganglia (DRG). Exercise training (20 minutes of wheel running, five times a week) after injury decreased the incidence of allodynia in the animals from 38 percent to 5 percent. Exercise also increased levels of GDNF and artemin. All the animals showed thermal hyperalgesia, and exercise did not change that. The authors conclude that exercise represents a noninvasive approach to increasing trophic factor levels in the spinal cord, with accompanying effects on neuropathic pain.
Elizabeth Dugan and colleagues at East Carolina University in Greenville, North Carolina, reported a consistent effect of exercise on rats with an excitotoxic spinal cord lesion that leads to over-grooming and thermal hyperalgesia. Animals that were intensively exercised (an hour of treadmill running, five times a week) showed reductions in both grooming and hyperalgesia. The mechanism of the effect remains to be determined.
To sleep, perchance to dream…
It is well documented that lack of sleep can worsen pain, and chronic pain can induce sleeplessness or unproductive sleep. To understand more about the neurobiological mechanisms of how sleep loss exacerbates pain, researchers from the lab of Clifford Woolf, Children’s Hospital Boston, and Thomas Scammell, Beth Israel Deaconess Medical Center, Boston, Massachusetts, developed an animal model of prolonged, moderate sleep restriction. The model, they say, more closely resembles life in the modern world than previous animal or human studies involving drastic sleep disruption. Alban Latrémolière outfitted the mice with EEG/EMG electrode hats and activity detectors to monitor sleep and movement. To model modest sleep deprivation, the researchers kept the mice awake for six hours each day during their morning light period. Normally, the mice would sleep for about one-third of that time. At the beginning, the mice want to be active, said Latrémolière, but by the end, “we need to poke them to keep them awake. It’s like staying up late to watch TV.” He and his colleagues found that the sleep deprivation over six hours was partially offset by increased sleep the rest of the day, so that the total amount of sleep over 24 hours was only reduced by 15-20 percent.
Even that had an impact: After one day of disrupted sleep, the animals were more sensitive to heat pain as measured in a hot plate assay, and sensitivity increased with subsequent days of lost sleep. After five days, the animals showed increased mechanical sensitivity (von Frey test), and an increased sensitivity to thermal stimulation in a tail flick test. Responses to pinprick or acetone application were unchanged. Pain sensitivity rapidly returned to normal when the animals were allowed to sleep normally. The results show that even partial sleep restriction over a few days increases pain sensitivity by several measures in mice. These changes involved both spinal (as indicated by the tail flick response) and supra-spinal mechanisms. “Similar mechanisms may be activated in chronic pain patients with disrupted or insufficient sleep and contribute to enhanced pain,” the authors conclude.
For next steps, Latrémolière said the lab is focusing on mechanistic studies, and taking an unbiased approach to look at the effects of sleep deprivation by measuring changes in gene expression, protein levels, and other parameters in spinal cord and DRG neurons. They also want to look at the consequences of long-term sleep loss and its effects on pain after injury.
As sleep affects pain, so pain affects sleep. To look at how pain changes sleep patterns, Chloé Alexandre in the Scammell lab used similar sleep analysis tools to study mice with chronic inflammatory pain after intraplantar injection of complete Freund‘s adjuvant, or neuropathic pain due to nerve injury. In mice subjected to spared nerve injury, the total amount of time awake or in rapid-eye movement (REM) sleep and non-REM (NREM) sleep was not changed compared to the pre-injury state. However, the sleep/wake periods were more fragmented, with more and shorter wake and NREM sleep bouts, and more instances of the mice waking up from REM sleep. In contrast, mice in the inflammatory pain model initially slept more at night, but by day 3 after injection came back to baseline sleep levels. Two weeks post-injection, the mice were more awake at night and slept more during the day. The results show that chronic neuropathic and inflammatory pain are associated with different changes in sleep architecture, the authors conclude, which may reflect distinct neural responses to different pain conditions. The ability to study in a detailed way sleep responses to injury in mice should lead to better understanding of the mechanisms underlying sleep disruption by pain.
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