Preoperative Efficiency of Conditioned Pain Modulation in Rats Predicts Recovery From Pain After Surgery
Rats with weak conditioned pain modulation (CPM), a measure of endogenous analgesia, experience longer recovery times from mechanical hypersensitivity following surgery compared to rats with stronger CPM, according to a study published in the April issue of Anesthesiology. The research, which is consistent with observations in humans, was led by Christopher Peters, Wake Forest University, Winston-Salem, US, and provides a new method for investigating CPM and postsurgical pain in animals. It also points to one mechanism, noradrenergic signaling, that may be involved in the relationship between CPM and resolution of pain after surgery.
“This is an impressive example of back translation [from humans to animals] in pain research,” wrote David Yarnitsky, Rambam Health Care Campus, Haifa, Israel, and Albert Dahan, Leiden University Medical Center, the Netherlands, in an accompanying editorial.
From people to rats
It was Yarnitsky’s own clinical work that inspired the current research. Chronic pain following surgery is a major problem that affects at least 10 percent, and possibly as many as 50 percent, of patients who undergo common surgical operations (Kehlet et al., 2006). Suspecting that individual differences in endogenous analgesia may play a role in these adverse outcomes, Yarnitsky has found that patients with lower CPM—lower induction of diffuse analgesia throughout the body following an intense, focal pain stimulus—prior to surgery were more likely to have chronic pain six months after thoracotomy (surgical opening of the chest; Yarnitsky et al., 2008). Preoperative CPM also predicts pain following abdominal surgery (Wilder-Smith et al., 2010).
To further examine the relationship between CPM and postsurgical pain, and to look for mechanisms underlying this association, Peters and colleagues modeled the two phenomena in rats. Overall, the research is an “effort to try to make the studies that we’re doing in rodents a little more translatable to humans,” said Peters.
To study CPM, the researchers used a paradigm in which capsaicin administered to the forepaw increases hind paw withdrawal thresholds to mechanical stimuli. To model postsurgical pain, the researchers performed partial ligation of the L5 spinal nerve. Nerve injury is a proposed risk factor for developing chronic pain, explained Peters, so “we wanted a model that had a neuropathic component … and that we knew would spontaneously recover,” he said. To examine the rats’ recovery, the researchers measured mechanical withdrawal thresholds in both hind paws until 70 days post-surgery.
Rather than simply analyzing mechanical hypersensitivity at arbitrary time points following surgery, the researchers instead used a statistical approach called growth curve analysis to determine the trajectory of recovery. This method allowed them to calculate an intercept, which reflects initial hypersensitivity following surgery, as well as a slope of recovery. Growth curve analysis is beginning to be used in clinical studies of pain, said Peters, and provides a more reliable measure of subjects’ experience with pain over time. “You can use it to look at the effect of interventions, as well as the impact of other perioperative factors such as stress, on aspects of recovery within individual animals,” he added.
Results indicated that individual animals varied significantly in the strength of their CPM response, as well as in their initial hypersensitivity and recovery following surgery. Overall, consistent with previous clinical findings, animals that showed a lower CPM response prior to surgery had a slower rate of recovery from mechanical hypersensitivity after surgery, as indicated by a significant correlation (r = 0.66) between CPM and slope of recovery. In contrast, the animals’ baseline level of hypersensitivity prior to surgery was not associated with recovery time.
“This suggests that the ability to engage the endogenous pain modulatory system is responsible for the recovery of chronic postoperative pain,” wrote Yarnitsky and Dahan.
Christopher Peters
A role for norepinephrine
The researchers then set out to examine the role of the noradrenergic system in the link between CPM and chronic pain following surgery. In the spinal cord, animal and human studies have shown that norepinephrine released from descending pathways suppresses pain, and painful stimuli are known to induce spinal norepinephrine release (Eisenach et al., 1996).
Consistent with a role for the noradrenergic system in CPM, capsaicin injection increased norepinephrine levels in the lumbar spinal cord, and intrathecal injections of the α2-adrenergic receptor antagonist idazoxan reduced, but did not eliminate, CPM, compared to saline-injected controls. Similar results were achieved following intrathecal injection of the toxin dopamine β-hydroxylase-saporin (DβH-saporin), which specifically ablates spinal noradrenergic fibers, two weeks prior to testing the strength of CPM; here, rats injected with immunoglobulin G (IgG)-saporin served as controls.
When DβH-saporin was administered to rats two weeks prior to surgery, the researchers found that recovery from nerve injury was slowed compared to controls. When DβH-saporin was instead administered seven weeks after the mechanical hypersensitivity induced by surgery had resolved, the pain response in both ipsilateral and contralateral hind paws was reinstated, suggesting that endogenous spinal norepinephrine is involved in the maintenance of mechanical hypersensitivity. These studies “established more of a causal role for the [noradrenergic system] in both endogenous analgesia and recovery,” said Peters.
Finally, to examine the role of the noradrenergic system in glial activation, a process implicated in chronic pain and mechanical hypersensitivity following nerve injury (Ji et al., 2013), the researchers examined markers of glial subpopulations. Preoperative disruption of the noradrenergic system by DβH-saporin increased the density of ionized calcium-binding adapter molecule 1 (IBA1, a specific marker of microglia) immunoreactivity in the ipsilateral spinal cord 70 days following partial spinal ligation. The researchers also observed an increased density of immunoreactivity to the astrocyte marker glial fibrillary acidic protein (GFAP) in both the ipsilateral and contralateral dorsal horn after DβH-saporin treatment prior to surgery. Taken together, these results suggested that spinal norepinephrine and noradrenergic tone might be inhibiting glial activation. Peters said that ongoing studies in his lab are examining whether the enhanced glial activation observed in DβH-saporin-treated animals contributes to the delayed recovery from nerve injury.
A number of unanswered questions remain. For example, there are many neurotransmitter systems that mediate endogenous analgesia, including opioids, serotonin, and oxytocin, said Peters. These all could play some role in promoting recovery from postoperative pain, he added, but the exact role of these other systems under certain conditions or in different types of injury is unknown.
In their editorial, Yarnitsky and Dahan also point out that future research is needed to determine exactly how and when to best target the noradrenergic system for treatment. The many factors that play a role in the human pain experience, such as the stress of surgery, type of rehabilitation strategy, and nature of underlying disease, complicate prospects to isolate specific mechanisms of pain inhibition, they added. Still, “[i]t is anticipated that this approach of translating and back translating on pain management relevant issues will provide answers to many open questions,” they concluded.
Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.
Image credit: Angel Vasilev/123RF Stock Photo
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