As an injury heals, the dissipation of pain over time is apparently not a simple return to normal. According to a study published September 20 in Science, the pain-free state requires active opioid receptor signaling that lasts months after the original injury. Brad Taylor at the University of Kentucky, Lexington, US, and colleagues found that well after mice had recovered from an injury, blocking their μ-opioid receptors (MORs) reinstated pain. These MORs had become stuck “on,” such that their signaling did not require opioid ligands. The researchers propose that interruptions to this active pain suppression could bring about chronic pain.
A puzzling condition, chronic pain develops in 10-20 percent of people after an old injury is seemingly resolved. Though researchers know something about how an injury initially induces pain-generating changes in the spinal cord, they presumed these changes were dismantled once the injury had healed. The new study shows that this is not so; instead, the original injury leaves the spinal cord poised to generate pain. This long-lasting susceptibility could set the stage for the delayed appearance of chronic pain.
“We thought there would be a time course that limited pain-related changes in the spinal cord,” said Jürgen Sandkühler of the Medical University of Vienna, Austria, who was not involved in the study. Sandkühler studies the synaptic alterations that occur in the spinal cord in response to painful stimuli (see PRF related news story). “This study suggests that these changes do not fade away by themselves, but that they are actively depressed by μ-opioid receptor activity for a really long time,” he told PRF.
Signs of long-lasting effects of the body’s own pain suppression mechanisms have been glimpsed before. A previous study from Taylor’s group found that the pain-suppressing effects of endogenous neuropeptide Y remained active weeks after an injury had resolved in mice (Solway et al., 2011). The new study finds a more complicated story, in which MOR signaling not only provided long-lasting pain relief, but also seemed to set up a state of opioid dependence.
“The good news is that tonically active μ-opioid signaling can keep pain under control,” Taylor told PRF. “But the bad news is that this feeds toward dependence.”
Blocking these receptors, then, could result in pain by removing their analgesic powers, or by provoking opioid withdrawal, of which pain is one symptom. Though the study does not settle on one of these mechanisms, it points to a potential downside of pain control through opiate receptors.
Reactivating pain
First author Gregory Corder and colleagues first found that MOR signaling in the spinal cord suppressed pain after an acute inflammatory injury to a paw. Left on its own, the injury took 10 days to resolve: Immediately after the injury, the mice exhibited mechanical hyperalgesia in the injured paw and displayed a reduced withdrawal threshold to touch. After 10 days, the hyperalgesia had disappeared, as indicated by the ability of the mice to endure the same touch stimulation they did prior to the injury. The researchers found that blocking opioid receptors with naltrexone right after the injury prolonged hyperalgesia, which lasted as long as the naltrexone application did. This indicated a role for MORs in resolving the acute phase of pain.
Next, the researchers discovered MORs were also at work well after the injury had healed. Giving naltrexone 21 days after the injury triggered hyperalgesia in the injured mice, but not in sham-injured mice. The degree of hyperalgesia depended on the dose of naltrexone, the overall effect involved MORs specifically, and the pain resurgence was seen in other pain models, such as surgical pain. Naltrexone could trigger hyperalgesia 200 days after an injury—the furthest out the researchers looked. Not only did the mice exhibit hyperalgesia at the injured paw, but they also showed it in the contralateral, uninjured paw, which suggests a widespread reworking of pain pathways involving the brain. This finding resembles the diffuse, whole-body pain reported by people with chronic pain.
Corder also noticed other odd behaviors in these mice, such as spontaneous jumping and shaking, which the team later recognized as potential signs of opioid withdrawal. This prompted them to think of the reinstated pain as a component of withdrawal, which suggested the mice had developed dependence on their own MOR signaling.
Traces of past pain
Looking for cellular reasons for this pain reinstatement, the researchers found that the injured mice had developed constitutively active MORs in the spinal cord, a state which promotes pain relief and has been linked to opioid dependence (e.g., Meye et al., 2012). Maintaining constitutive MOR activity may be key to avoiding the development of chronic pain. “From a pharmacological point of view, the role for [constitutively active MORs] in pain is an extremely important and novel finding,” Corder said.
Prior to naltrexone, the researchers found that, compared to sham-injured mice, the injured mice exhibited enhanced signaling through two molecules crucial to pain generation: the NMDA type of glutamate receptor and adenylyl cyclase I (AC1), an enzyme that converts ATP to cAMP. Calcium admitted through NMDA receptors spurs AC1 to produce a spike in cAMP, which drives pain. Indeed, naltrexone given to previously injured mice prompted a bloom of cellular signs of pain in the spinal cord, including expression of phosphorylated extracellular signal-regulated kinase (pERK), calcium increases in the cell, and an overshoot of cAMP levels. This suggests that the initial injury primed the NMDA-AC1 pathway to generate pain upon the interruption of MOR signaling.
The researchers suggest two potential mechanisms behind the pain reinstatement. The original injury-induced remodeling of pain pathways that produces hyperalgesia is maintained but masked by constitutive MOR activity. Thus, blocking MORs would unleash this pain. Alternatively, long-term potentiation could develop anew at nociceptive synapses upon MOR blockade, which would result in pain. To distinguish between these, the researchers are recording from neurons in the spinal cord to track when and how the synaptic changes mediating pain take root.
Chronic question
Though the persistent traces of a past injury offer an explanation for the emergence of chronic pain, it seems odd that the nervous system would hold on to signs of a past injury for such a long time. “Maybe the basic principles of memory formation are present at almost all synapses in the central nervous system,” Sandkühler said. To rid itself of unnecessary “memories” of pain, then, the nervous system may have evolved a way to actively suppress them.
Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.
