If you put your hand on a hot stove, you will stop touching it immediately. Why? Your brain quickly processes two things: the burning sensation on your hand and your responsive feeling of not liking it, which drives you to remove your hand from the stove.
Research pertaining to this reaction has focused on the latter process, that is, the sensory component of pain. The mechanisms underlying how a painful stimulus is detected and processed by the spinal cord and brain have been the basis of several therapies for both acute and chronic pain. Yet, the unpleasant feelings we experience in response to pain may also be important to pain management.
“Neuroscientists are still unraveling how neural activity across the brain produces the multidimensional experience of pain,” Biafra Ahanonu, PhD, a neuroscientist and researcher at Stanford University, tells PPM.
By peeking into the brains of mice, Dr. Ahanonu, as well as Gregory F. Corder, PhD, assistant professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania, and their colleagues hope to change that. Recently, they identified a group of brain cells involved in processing pain-related emotions and demonstrated how these neurons motivate subsequent behaviors in response to pain.
The scientists centered their study on the amygdala, the region of the brain involved in producing emotion. They recorded brain activity using small miniature microscopes mounted on each mouse’s head. During the study, the mice were permitted to roam freely; occasionally, the scientists poked and prodded the mice with various unpleasant stimuli (such as drops of hot/cold water and pinpricks) to see which neurons were activated.
“We identified a group of neurons in a brain region called the amygdala that responds to noxious (potentially harmful or damaging) stimuli. More activity in these pain neurons [predicted] greater or more vigorous pain behavior,” Dr. Ahanonu explains.
Next, the team set up a walking track made up of three zones, each set at a different temperature: One zone was very cold; one zone was hot; and one was of a modest temperature. Some mice were injected with a drug, clozapine-N-oxide, which specifically activated a receptor that inhibited the pinprick-responsive cells in the previously identified neural circuit. The team found that mice who did not receive the drug learned very quickly to avoid the very hot and cold zones of the track, whereas the mice on clozapine-N-oxide medication continued to visit all three areas of the track.
Finally, the scientists induced sciatic nerve injury (a type of spine/back pain) in a subset of their mice, tracking the dynamics of the previously identified neural circuit before and after the onset of neuropathic pain. According to the research, “a hallmark of chronic neuropathic pain is the appearance of allodynia (that is, pain that occurs even with non-painful stimuli) and hyperalgesia (that is, an abnormal increased sensitivity to pain).”
The key finding of the intervention was that the mice experienced increased activity within the pain circuit in response to light touch, in addition to withdrawal reflexes and other pain-aversive behaviors. Researchers also found that the injection of clozapine-N-oxide circumvented pain-aversive behaviors while maintaining reflexive responses to the pain.
“This intact reflexive response is an important finding, as it means the unpleasantness of pain could be reduced without sacrificing the critical protective reflexive behavior,” Dr. Ahanonu explains. “A key next step [will be] to identify whether these cells have unique biological signatures, such as expressing specific receptors, that would allow us to therapeutically target them using small molecules, biologics, or other methods.”
“Pain is both a sensory and affective experience. This alone causes a lot of controversy despite the research that is currently available to support this claim,” says David Cosio, PhD, a psychologist in the Pain Clinic at the Jesse Brown VA Medical Center in Chicago, and a member of the PPM Editorial Advisory Board. “This study begins to refine the neurobiology underlying the complexity of the pain experience in the hopes that it may help develop more effective analgesic therapies,” Dr. Cosio adds.
“Those suffering from acute and chronic pain should see these results as another step toward our understanding of the mechanisms that produce the pain experience, and, in the future, may lead to the discovery of new pain therapies,” Dr. Ahanonu says. Heurged the need for treatments that are “effective, scalable, and have minimal side effects” in the face of both the ongoing opioid epidemic, and the psychological and financial burden caused by acute and chronic pain.