Linking Early Life Stress, Pain, and Exercise
Recent evidence suggests that early life adversity (ELA), such as childhood abuse or neglect, can lead to abnormal stress responses as well as abdominal and pelvic pain many years down the road. Several studies presented at the 44th annual meeting of the Society for Neuroscience held in Washington, DC, US, from November 15-19, used rodents to dig deeper into these phenomena, finding that ELA produces stress-induced, sex-specific increases in visceral nociception in adulthood that are improved by exercise.
Early stress equals later sensitivity
At a Tuesday afternoon poster session Dawn Kennedy Prusador of the University of Oklahoma, US, followed up on previous work from her group showing that in female rats, administration of unpaired odors and shocks during the second week of postnatal life (modeling unpredictable early life trauma) leads to visceral hypersensitivity, measured by a visceromotor response to colorectal distention, in adulthood (Chaloner and Meerveld, 2013). This effect was estrogen dependent. In contrast, when young females are exposed to paired odors and shocks (modeling predictable early life trauma), visceral nociception in adulthood is unaffected. Neither model affects pain in male rats.
In the new research, Prusador and colleagues added another layer of complexity, examining the effect of early life stress on the visceromotor response in adulthood after adults were exposed to water avoidance stress (WAS). A single day of WAS increased the number of abdominal contractions in response to colorectal distention in all female rats, with those who had experienced unpredictable ELA as newborns showing the highest response. Seven days of WAS produced similar results, although both predictable and unpredictable ELA significantly increased abdominal contractions. In males, on the other hand, WAS produced increased colonic sensitivity, but neither form of ELA exhibited an effect.
The results suggest that ELA “unmasks” an exacerbated response to an adult stressor in females but not males. In addition, the results provide, for the first time, a model that recapitulates the female predominance of stress-induced chronic visceral pain in humans, said Prusador.
Angela Pierce from the University of Kansas, US, also examined the effect of early life stress on visceral pain later in life. Using a different ELA paradigm—neonatal maternal separation—Pierce found that female mice separated from their mothers for three hours per day for the first three weeks of life displayed increased bladder sensitivity, reflected by increased abdominal muscle activity during bladder distension, and higher rates of micturition (urination) at eight weeks of age. Compared to mice that were not stressed at birth, the ELA mice also showed elevated mast cell degranulation in the bladder and vagina, as well as higher levels of the mast cell signaling receptor PAR-2, indicative of increased hypothalamic pituitary (HPA) axis activation.
Since ELA can disrupt the HPA axis and lead to chronic pain, the researchers then examined the effect of a known modifier of the HPA axis, voluntary exercise, on the bladder hypersensitivity and dysfunction in ELA mice. Consistent with their hypothesis, four weeks of voluntary wheel running improved bladder hypersensitivity, micturition, and mast cell degranulation. Pierce’s lab mate Isabella Fuentes performed similar studies in male mice. On the whole, males exposed to ELA displayed many of the same changes as females, and these abnormalities were also improved by wheel running.
The two sexes did diverge in one respect: the level of anhedonia (as measured by the amount of a highly palatable sucrose consumed), a symptom of depression in which normally enjoyable activities are no longer pleasurable. Sedentary ELA males showed higher levels of anhedonia than controls by drinking less sucrose, an effect that was abolished by exercise. Surprisingly, sedentary ELA females drank more sucrose than controls, though exercise improved sucrose consumption in both the stressed and non-stressed animals. Taken together, the results suggest that exercise can improve visceral pain as well as comorbid depression symptoms.
Exercise for neuropathic pain?
In a neighboring poster session on spinal cord injury (SCI), Timo Nees from the Heidelberg University Hospital, Germany, examined the effect of treadmill training in a mouse model of SCI that reproduces the neuropathic pain present in more than half of injured patients. A moderate contusion to the T11 spinal cord of females, which impaired but did not eliminate mobility, produced hindpaw mechanical and thermal hypersensitivity at lower levels of stimulation, but hyposensitivity at noxious levels. Although the findings of both hyper- and hyposensitivity may seem contradictory, light touch and noxious mechanical stimuli are not mediated by the same sensory pathways, said Nees. “There seem to be differential responses of these different pathways to injury and training,” he said. In addition to the altered sensitivity, the SCI mice also displayed spontaneous pain-related behaviors, as well as increases in the density of peptidergic C-fibers in laminae III-IV of the spinal segments located below the injury.
Moderate treadmill training (administered in two 15-minute sessions five days per week) beginning in the second week after injury reduced the mechanical allodynia, suggesting that physical activity could be used to treat neuropathic pain following SCI. In fact, the benefits of exercise were apparent after only six days of training and persisted throughout the remaining four weeks of training. However, these effects seemed to be modality specific; the thermal abnormalities were not improved after physical activity. Paralleling the improvements in mechanical hypersensitivity, treadmill training also decreased the density of C-fibers resulting from the SCI.
Taken together, the findings suggest that physical activity may be a means to treat some kinds of neuropathic pain following SCI. To identify the neural substrate underlying the analgesic effects of exercise, the researchers plan to use transgenic mouse models to selectively manipulate specific spinal and sensory subpopulations.
Not all evidence suggests exercise helps pain. Tayler Sheahan from Washington University in St. Louis, US, presented a poster on Wednesday morning suggesting that short-term exercise doesn’t improve inflammatory or neuropathic pain. Neither two nor 12 hours of voluntary wheel running per night for 10-12 days improved acute inflammatory pain induced by hindpaw injection of formalin. Similarly, neither exercise paradigm improved the mechanical hypersensitivity induced by a spared nerve injury (SNI) to the sciatic nerve, even though both the injured and sham mice ran the same distance. Physical activity also failed to improve the muscle wasting, hindpaw denervation, or epidermal thinning caused by SNI.
The finding that exercise did not improve mechanical hypersensitivity following peripheral nerve injury contradicts much of the existing literature. Sheahan noted that animals exercised voluntarily in the current study, while many of the prior studies used forced exercise paradigms, where stress-induced analgesia could play a role in the observed effect. In addition, it is possible that a longer period of exercise is needed to ameliorate the mechanical hypersensitivity, she said, a possibility the researchers will test in future studies.
Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.
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