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The Physiology of Pain

The feeling of pain involves complex mechanisms that researchers are trying to figure out—as 50 million people in the U.S. continue to suffer from chronic pain. 
By Lauren Arcuri 

Feature_Physiology-of-PainPain is a universal human experience, one that is protective at its core: Acute pain warns us of harm and prevents us from damaging our bodies, or limits that damage. We experience pain as unpleasant, and it generally signals us to move away from a dangerous situation or stimuli. Acute pain often disappears fairly quickly once we’re safe.

But acute pain doesn’t always resolve as expected, especially if it’s part of a disease process or begins with an injury that isn’t treated appropriately and swiftly. An estimated 20% of the U.S. population—50 million people—suffered from chronic pain in 2016, according to the Centers for Disease Control and Prevention (CDC). And, that number may have increased during the pandemic.

Chronic pain is one of the most common reasons U.S. adults seek medical treatment. The lack of adequate medical treatment for chronic pain is also a catalyst that fuels the ongoing “opioid epidemic,” a massive increase in addiction to prescription and/or illegal opioids and the cause of more than 100,000 overdose deaths in 2021, according to the CDC (see sidebar on page 33).

Researchers are working hard to understand the complex mechanisms that underlie our experience of pain. According to the International Association for the Study of Pain, pain is defined as an “unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” There are three types of pain classified by cause. 

The pain you feel when you stub your toe or put your hand on a hot pan is called nociceptive pain. A sensory neuron—or nociceptor—transmits an electrical impulse to the spinal cord and then to the brain, where it is experienced as pain. 

Inflammatory pain results from infection or tissue injury, leading to activation of the immune system. The body produces proinflammatory mediator molecules that include cytokines, chemokines, nerve growth factors and more. Both of these types of pain are protective.

The third type, pathological pain, is not protective and often results from peripheral nerve damage. “In some cases of neuropathy, nerves begin to fire spontaneously, leading to pain sensation in the absence of a stimulus. In other forms of dysfunctional pain after nerve injury, the central nervous system relays pain messages to the brain, regardless of input from peripheral nerves,” says Bradley Taylor, PhD, professor of anesthesiology at the University of Pittsburgh.

“One thing that would help would be to find a biomarker for chronic pain. “If you want to treat, you need an endpoint that you can target.”

Allan Basbaum, PhD

Our experience of pain is often described as made up of two components, Taylor says. One is a sensory component where the noxious stimulus—anything from a bee sting to hitting your elbow on a doorjamb—activates nociceptors in the skin. Or, if the stimulus comes from inside the body, receptors within the organ or area of injury are activated, leading to electrical impulses that travel first to the spinal cord and then up to the brain.

The spinal cord isn’t a mere relay station for the electrical input. “Really, there’s a lot going on in the spinal cord before it sends the brain signals that are rich in information,” Taylor explains. 

The second component of pain is affective and cognitive in nature, where the brain experiences the sensation of pain as something unpleasant, a form of suffering. While this experience is generated in the brain, it’s influenced by the specific nature of the message it receives from the spinal cord, according to Steve Prescott, MD, PhD, professor at the Hospital for Sick Children and University of Toronto in Canada. “Pain is a really multidimensional experience, and while your experience of the emotional component of it is dependent on cortical processing, it’s typically triggered by sensory input from the periphery,” he says.

Chronic pain: a central nervous system gone awry

According to the World Health Organization’s International Classification of Diseases, chronic pain is pain that lasts more than three months. Our pain systems become sensitized for days to weeks as we heal from an injury. “There’s inflammation around the tissues and they experience pain from even light touch or movement,” Taylor says. 

Sometimes those sensitization processes don’t go away and the person is in a state of chronic pain hypersensitivity. Some chronic pain sufferers experience pain even in the absence of touch or movement, Taylor adds. The induction of pain by a normally innocuous stimulus is the major problem that people who have chronic pain experience. 

When pain persists after an injury or infection has healed, changes in the central nervous system may have occurred. “It’s somewhat controversial, but I’m a firm believer that chronic pain can exist completely in the central nervous system,” Taylor says. In these cases, pain is no longer driven by nerves at the site of the initial injury, but instead by pathological changes in the brain or spinal cord. 

“I believe that the pain experience is governed in a very homeostatic fashion,” Taylor says. “There are excitatory systems that drive the initial response to pain and pain sensitivity, and there are very powerful endogenous inhibitory systems within the body that inhibit the pain experience. These work together as a rheostat.” If inhibitory systems function properly, then pain should resolve. “In my laboratory, our overarching concept is that chronic pain pathology involves not only a foot stuck on the accelerator, but also a dysfunction with the brake—the inhibitory system.”

Allan Basbaum, PhD, professor and chair of anatomy at the University of California, San Francisco, agrees. He compares chronic pain—at least that produced after nerve injury—to epilepsy, a disease process that involves a loss of inhibition in the cortex, which manifests as seizures. “In neuropathic pain, comparable changes occur,” he says. “There’s loss of inhibition at different levels, particularly in the spinal cord. There’s hyperexcitability. There’s new connections being made, new genes being induced—all these constitute features of the disease.”

“In my laboratory, our overarching concept is that chronic pain pathology involves not only a foot stuck on the accelerator, but also a dysfunction with the brake—the inhibitory system.”

Bradley Taylor, PhD

Some cases of neuropathic pain occur after damage in the central nervous system (such as after spinal cord injury, post-stroke and in patients with multiple sclerosis). Here, the “disease” of pain is independent of inputs. In the case of neuropathic pain that is peripherally induced, such as in diabetic neuropathy where there is nerve damage, there is still a peripherally located driver of the pain, but “it’s now engaging an altered central nervous system,” Basbaum says. 

Ru-Rong Ji, PhD, professor of anesthesiology at Duke University School of Medicine in Durham, North Carolina, believes that chronic pain may be caused by dysregulation of glial cells, the supportive nervous system cells that provide nutrition, immune support, insulation and protection to neurons. Glial cells include microglia and astrocytes, which are found throughout the spinal cord and brain and help maintain the homeostasis of the nervous system.

Ji and other researchers have found that during the transition stage from acute to chronic pain, there is activation of certain signal transduction pathways that involve glial cells. This activation switches them from their anti-inflammatory, supportive role to a pro-inflammatory one. The glial cells then produce inflammatory mediators, cytokines and chemokines that increase the intensity and amplitude of pain and enhance its duration, Ji says.

“It is a major shift in thinking that glia may be a driver of chronic pain,” he says. Glia in the central nervous system may underlie a specific type of central nervous system inflammation called neuroinflammation.

Those same glial cells seem also to contain the potential to resolve chronic pain. Resolvins are a specific family of mediator molecules that are part of the “brake” or inhibitory system. Enzymatically generated in glia from the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil, they are thought to be involved in the active phase of resolution of inflammation. “Resolvins are very exciting potential mediators,” Ji says. “They produce a very potent analgesic effect at much lower doses than morphine and without any side effects.”

New approaches to treating chronic pain

Chronic pain is not just an extension of acute pain. The mechanisms underlying it are different. Thus, treating it merits a different approach: Instead of treating pain as a symptom by blocking the pain transmission pathway from periphery to brain, researchers hope to address the underlying disease process that is keeping the pain sensation alive. “We know that some treatments like non-steroidal anti-inflammatory drugs and opioids that are effective for acute pain only give transient mild relief for chronic pain, if at all, and may even make it worse in some cases,” Ji says. Steroids can reduce inflammation-induced pain temporarily, but they have potent side effects and can’t be used safely long-term. Steroids have also been shown to delay the resolution of inflammation.

The longer the chronic pain process continues, the more difficult it is to resolve. “We have started to ask: How can we promote resolution of recovery?” Ji says. “Neuromodulation and spinal cord stimulation have been used for years, but usually as a last resort. But neuromodulation can be extended to different regions—not just the spinal cord, but the dorsal root ganglia and peripheral nerves. Vagus nerve stimulation can help control inflammation system-wide, and exercise can help modulate sympathetic tone.”

Ji believes that fish oil, which contains the precursors to resolvins, in concert with neuromodulation or exercise, can help the body produce resolvins and move toward a state of resolution of chronic pain. Treatments such as acupuncture have long worked to help resolve chronic pain, but now, Ji says, we have a better understanding why: They may reduce inflammation in the body.

Basbaum agrees that neuromodulation has potential to treat chronic pain at its root, even though researchers don’t yet fully understand the mechanisms by which it works. “It’s hard to have a placebo-controlled trial because patients often can tell when they’re being stimulated. But some of these approaches, in particular dorsal root ganglion stimulation, have been remarkable for some patients,” he says. Transcranial magnetic stimulation of the motor cortex also works in many cases. “Why would you stimulate the motor cortex to relieve pain? Stimulating the somatosensory cortex doesn’t work, but the motor cortex does. How does it work? We don’t really know,” he says.

These approaches have the potential not just to relieve ongoing pain, but also to reverse dysregulation and promote pain resolution. 

“The glial cells then produce inflammatory mediators, cytokines and chemokines that increase the intensity and amplitude of pain and enhance its duration.”

Ru-Rong Ji, PhD

Taylor’s lab studies how interconnections between interneurons in the dorsal horn of the spinal cord can change after injury. “The changes in circuitry may explain the transition from acute pain to chronic pain,” he says. The lab has focused on a neuropeptide receptor system that they think may be a potential target for chronic pain. It’s called neuropeptide Y (NPY). “We’ve been finding for 25 years now that application of NPY to the spinal cord can inhibit pain transmission in rodents,” he says. And along the way, “we started to realize that what we were doing was to mimic a natural, endogenous pain inhibitory system.”

To better understand the mechanisms of action of NPY, Taylor’s lab is using chemogenetics and optogenetics to manipulate the activity of the neurons that express specific types of NPY receptors found in the dorsal horn of the spinal cord, most notably the Y1R type. When they selectively ablated Y1R interneurons in rodents, the intensity of pain-like behaviors after peripheral nerve injury were reduced. They concluded that spinal Y1R interneurons can contribute to pathological pain—and present a potential target for treatment of chronic neuropathic pain.

“After an injury, connections between spinal neurons change in such a way that touch information becomes cross-wired and enters into the pain pathways, so that even a light touch activates Y1R-expressing neurons, producing pain,” Taylor says. There are some challenges with turning NPY into a therapeutic for humans, as it can have off-target effects on hunger and blood pressure, but his lab is searching for a solution. “We’re now conducting studies to understand how endogenous opioid and NPY receptor mechanisms might interact to prevent chronic pain.”

The Taylor lab is also interested in repurposing existing drugs to see if they work for chronic pain. They are studying a specific class of drug that targets peroxisome proliferator-activated receptors (PPARs), currently used to treat diabetes, which shows promise as an analgesic for chronic pain. The thiazolidinedione class of drugs approved by the U.S. Food and Drug Administration include rosiglitazone and pioglitazone and target a specific isoform of PPAR called PPARγ. The lab discovered that PPARγ mRNA and protein are expressed in the dorsal horn of the spinal cord and that PPARγ agonists reduce inflammatory and neuropathic pain—likely through actions at the spinal glia. “We’re hoping to move those studies to clinical trials,” Taylor says. 

While the search continues for potential therapeutic treatments, one thing that would help, Basbaum says, would be to find a biomarker for chronic pain. “If you want to treat, you need an endpoint that you can target,” he says. Ideally, this biomarker would arise from a more complete understanding of the mechanisms that cause chronic pain in the body—an understanding that researchers are getting closer to day by day.  

This article was originally published in the March 2022 issue of The Physiologist Magazine.

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Living with Chronic Pain during the Opioid ‘Epidemic’

The overprescription of opioid drugs in the past several decades has led to a consensus against their routine use for chronic pain. “The consensus now is that if a patient comes to you and is diagnosed with chronic pain, or pain lasting more than three to six months, you don’t want to start them on opioids,” says Bradley Taylor, PhD, professor of anesthesiology at the University of Pittsburgh.

While that approach seems sound, what about chronic pain patients who have long used opioid medications to control their pain and who are not abusing them? Kelly Hills, a bioethicist in Boston, is one such patient. She’s had complex regional pain syndrome for 17 years after several bad car crashes. 

Hills’ pain has been controlled on a relatively low dose of opioids, but she must jump through time-consuming hoops to continue her prescription, even though her care team agrees it is the best and only option for her. She’s tried other appropriate possibilities, including physical therapy, aquatic therapy and stellate ganglion blocks, in which a local anesthetic is injected into the stellate ganglion nerve in the neck. 

To continue her pain relief, Hills must meet with her prescriber every three months, a pain psychiatrist twice a year and a separate chronic pain specialist once a year. And her refills aren’t automatic even after nearly two decades: Every month she must request that her primary care physician refill the medication and hope that her pharmacy either has the prescriptions in stock or can get them in time for her to receive them without missing doses.

In an effort to curb overprescription of opioids, physicians must now participate in a prescription data monitoring plan, or PDMP, where all of their opioid prescribing must be compared against other physicians monthly. If a physician has too many chronic pain patients, they may have to justify their prescribing. 

Taylor says that for some chronic pain patients who take opioids, it’s important to recognize the significant damage that can be done by forcing them off their medication. “While the consensus is that you don’t want to start patients on opioids, if an established chronic pain patient has been taking opioid medications responsibly for a long time, then it may be best to just leave them be,” he says. “In the absence of large-scale research trials indicating otherwise, we cannot rule out the possibility that opioids can manage their pain for long periods of time.”

Hills feels the term “opioid epidemic” is a misnomer. “It creates this impression of a reality that doesn’t really exist, that people get medications from their prescribers to sell them on the street. That’s a really common misconception,” she says. “It’s really an ‘overdose epidemic.’ That’s what people are concerned about. When we call it an opioid epidemic, we create a stigma around anyone who needs to use opioids for pain management.

“I think what most people miss is the idea that a war on opioids is a choice,” she continues. “We are choosing to ignore disabled people who need pain management. And we could make life a whole lot better for a whole lot of people, if we just changed the way we thought about it.”