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Responses to External Threats and Sustained Pain Travel Via Different Neural Circuits

January 24, 2019
New study outcomes in mice suggest that common pain measurement tools may be inadequate.

with Qiufu Ma, PhD

Different neural pathways appear to underlie reflexive responses to external threats and coping responses to sustained pain, according to a new animal study.1 These findings suggest that traditional methods of measuring pain, which rely on reflexive responses, may be inappropriate for chronic pain assessment. The research, along with previous work, has important implications for the 22% of the world’s primary care patients living with chronic debilitating pain, according to the World Health Organization.2

Reflexive-defensive responses prevent or limit injury. For instance, think of the classic example of the finger on a hot stove that is quickly yanked away. If this first-line response does not prevent tissue damage, another type of pain response (coping) is triggered to soothe the persistent pain from the injury—such as licking the burned finger.

“The ongoing persistent licking around the injured area seen in mice may more closely reflect the ongoing suffering that humans experience,” lead author Qiufu Ma, PhD, professor of neurobiology in the Blavatnik Institute at Harvard Medical School and researcher at the Dana-Farber Cancer Institute, told PPM. “The loss of this behavior is not detected by measures of the initial quick withdraw response or other forms of defensive reactions to external threats. This suggests that there are separate circuits or neural pathways in our bodies—one [that] deals with reflex/defense and one [that] deals with ongoing injury.”

The idea of two separate pathways makes a lot of sense, according to Dr. Ma. “One pathway deals with avoiding injury. The other kicks in when you’ve failed to protect your skin. This is the second-line coping behavior for reducing suffering. These two behaviors combined together promote animal survival,” he said.

New study outcomes in mice suggest that common pain measurement tools may be inadequate. (Source: 123RF)

Neurons in Pain Response

By genetically manipulating mice, researchers were able to mark specific spinal neurons, turning them on and off. They studied the mice using behavioral tests involving noxious skin stimuli (pinching, for example) to understand the neural circuits involved in reflexive and coping pain responses. In particular, they looked at spinal neurons that coexpress the TAC1and LBX1 genes. While the role of these neurons was unclear, their connections to one part of the brain, the medial thalamic nuclei, that processes “unpleasantness evoked by sustained, intensely noxious stimuli,” suggested that they could play a role in coping responses to sustained pain.

When the researchers turned off these spinal neurons, the mice lost their “licking” coping behavior in response to tissue injury. They also failed to learn how to avoid the stimuli that produces sustained pain in humans. However, the mice still exhibited reflexive-defensive reactions. The loss of sensitivity to prolonged pain in these mice mimic observations from humans with damage to the medial thalamus (due to stroke or tumors, for example), the area of the brain responsible for much of pain processing. Individuals with this type of brain damage do not experience prolonged pain. These findings confirm a role for these spinal neurons in—and a separate circuit for—pain coping behaviors related to prolonged irritation or injury.

“What was particularly striking for me is that pain rating reported by humans almost matches the time course of the licking of the animals,” said Dr. Ma.

In light of these findings, pain testing that relies on reflexive responses may not be useful for assessing long-term pain or treatments for this type of pain. “For acute pain measurement, for many years we’ve relied on first-line reflex or other forms of defensive reactions. We always measure the lowest threshold of mechanical stimulation, like with a von Frey filament (mechanical nociceptive threshold test) or the shortest time of exposure to heat or cold that causes withdrawal,” said Dr. Ma.

Touch-Evoked Dynamic Mechanical Pain

In earlier work,3 Dr. Ma and his team of researchers investigated touch-evoked dynamic mechanical pain—commonly suffered by patients with neuropathic pain (such as that due to nerve damage caused by postherpetic neuropathy). In addition, up to half of these patients with neuropathic pain experience evoked pain. Even the lightest touch can cause excruciating pain, making it difficult for patients to even put on clothing, for example.

According to Dr. Ma, touch-evoked dynamic mechanical pain is one of the toughest types of pain to treat. His team has demonstrated that touch-evoked dynamic allodynic mechanical pain cannot be detected using von Frey filaments. Since the majority of laboratories studying pain use this type of testing, they may not be adequately measuring more clinically relevant neuropathic pain (ie, dynamic allodynia), explained Dr. Ma.

This distinction could account for some of the poor translation that occurs between preclinical studies and the development of effective pain medications. Researchers simply may not be measuring the pain that is of greatest concern to patients. Identification of the neural underpinnings of sustained pain could lead to better ways to measure clinically relevant pain and ultimately better pain treatments.

Last updated on: February 7, 2019
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