Responses to External Threats and Sustained Pain Travel Via Different Neural Circuits – Practical Pain Management – By Kerri Wachter with Qiufu Ma, PhD – Jan 2019
New study outcomes in mice suggest that common pain measurement tools may be inadequate.
Different neural pathways appear to underlie
- reflexive responses to external threats and
- coping responses to sustained pain
I’m surprised this hasn’t been obvious to researchers because it’s certainly clear to pain patients. The experience of acute pain, like stubbing your toe, is wildly different than that of long-term pain, like failed back surgery, so it seems obvious to me that different aspects of our nervous system are involved.
These findings suggest that traditional methods of measuring pain, which rely on reflexive responses, may be inappropriate for chronic pain assessment.
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
“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 deals with reflex/defense and
- one 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.
Neurons in Pain Response
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.
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.
These findings confirm a role for these spinal neurons in—and a separate circuit for—pain coping behaviors related to prolonged irritation or injury.
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
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.
Different endpoints decided upon and used in experiments can determine the results of a study. By using different surrogate endpoints, a study’s results can be completely different.
Below is an even more technical explanation of the same study:
The response to a painful stimulus generally consists of two phases:
- a quick withdrawal from the stimulus,
- followed by behaviors such as rubbing or licking of the injured area to help ease the suffering.
While these responses are well recognized by pain researchers, whether the same neuronal circuits underlie them remains poorly understood.
A Neural Pathway for Soothing Sustained Pain
New research puts forth spinal TAC1-lineage neurons as responsible for behaviors that help mice “cope” with painful stimuli; exactly what those behaviors represent, and relevance of findings to chronic pain, remain uncertain
Now, a new mouse study led by Qiufu Ma, Dana-Farber Cancer Institute and Harvard Medical School, Boston, US, identifies spinal neurons marked by the expression of tachykinin (TAC1) during development as responsible for what the researchers describe as “coping” behaviors associated with sustained pain, including rubbing and licking of the hind paw, over a period of several minutes.
Further, selective ablation of the TAC1-lineage neurons resulted in a loss of these behaviors, as well as a loss of conditioned place aversion evoked by pinch, but without affecting reflexive defensive reactions to external threats. Conversely, optogenetic activation of the neurons was sufficient to produce soothing behaviors in the animals.
Whether the behaviors examined in the study represent “coping” has become a matter of debate, and the relevance of the findings to chronic pain also awaits further study.
Nevertheless, what Ma hopes most for his new paper is that it spurs more discussion about the measurement of acute and chronic pain.
It’s time to “revisit current acute pain measurement in animal studies, and it’s urgent for future studies to distinguish sensitized reflexes versus sensitized pain under chronic pain conditions,” Ma said.
Different responses, different pathways
To investigate behaviors produced by intense and sustained mechanical pain, the researchers, working with Robert LaMotte and Nathalie Malewicz at Yale University School of Medicine, New Haven, US, employed a translational approach using an alligator clip to pinch the skin of both human subjects and mice.
The former were asked to report the pain felt upon clip application, and they reported a peak maintained pain intensity within 15 seconds, which corresponded with the time course of peak licking episodes observed in wild-type mice.
“It was very interesting to see that the sustained pain rating in humans following the pinch almost temporally matched the sustained ongoing licking behavior in mice, suggesting that skin pinch-evoked licking could be used to measure sustained mechanical pain in animal studies,” said Ma.
It’s creepy to read about how much thinking is going into devising ways to inflict pain on mice that correspond to the types of pain a human feels.
If pain truly is biopsychosocial, then no animal model could even come close. By conducting these “chronic pain” studies on animals, they’re essentially admitting that the biological aspect of pain is the initiator and a significant portion of the continuing pain we feel.
Is it coping?
The use of the term “coping” to describe the behaviors of the mice in response to sustained pain is problematic to some, but Ma acknowledges this.
“In this study we used ‘coping’ to describe an ongoing behavior towards an injured area that tries to reduce the suffering caused by inescapable sustained pain. We struggled to find a better word to describe these behaviors,” according to Ma.
Regardless, he hopes his work will spark further conversation about the best way to assess such animal behaviors evoked by stimuli that also produce sustained pain in humans. “Current approaches that use withdrawal reflexes or defensive reactions in animals are not ideal, as they likely reflect innate responses to external threats or, at best, the first sharp pain percepts and not the suffering components of sustained pain,” Ma told PRF.
Looking to the periphery
Ma and colleagues believe their findings show, at the spinal level, a functional segregation of neurons
- that process reflexive, defensive responses from those that
- regulate soothing behaviors in the presence of sustained pain.
Whether or not there is an interdependent relationship between peripheral TRPV1 nociceptors and spinal TAC1-lineage neurons remains to be addressed
Interestingly, the researchers say that by examining more than only reflex assays, their results cast doubt on a previously held conclusion that MRGPRD nociceptors are required to drive sustained acute mechanical pain (Cavanaugh et al., 2009), since they showed in their new study that it was TRPV1 neurons that were critical for this.
Identifying the pathways required for coping behaviours associated with sustained pain.
Huang T, Lin S-H, Malewicz NM, Zhang Y, Zhang Y, Goulding M, Lamotte RH, Ma Q
Nature. 2019 01; 565(7737):86-90.