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In 2020, the International Pain Society IASP published a new version of the definition of pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or an experience similar to it. The new definition broadens the connotations of pain, emphasizing that pain is subjective and influenced by many biological, psychological and social factors.
Chronic pain is a major global health problem, but years of preclinical research on pain have not produced successful new drugs for non-opioid pain treatment. In 2019, the NIH's Pain Symposium raised a discussion of animal models of pain and behavioral experiments: To what extent are animal models of pain similar to patients with pain clinically? Do behavioral experiments on pain reliably reflect the feeling and emotional experience of pain?
Based on the above background, Professor Ma Qiufu of Harvard Medical School published a viewpoint article in Neuron on January 10, 2022, proposing that the somatosensory system can be functionally divided into two subsystems, which drive external and internal sensory behaviors, respectively, and demonstrate the existence of a neuroanatomical basis for driving external and internal sensory behaviors at the level of primary sensory neurons, spinal cord, paraarm nucleus, and forebrain, as well as how the external and internal sensory systems interact in pain states. In addition, the functional breakdown of external and internal sensations is proposed to bring enlightenment to pain research.
The authors argue that external sensations are unconscious or conscious perception of external threats and the production of reflexive or defensive behaviors, such as evasion and jumping, to avoid irritating and damaging the body; when the integrity of the body has been damaged, the body produces persistent pain internal sensations, producing self-caring behaviors, such as licking, to relieve the pain of persistent pain.
Figure 1: Nociceptive stimuli cause extrinsic and intrinsic sensory behaviors
Studies of patients with brain injury suggest functional segmentation of the somatosensory system
Patients with lateral thalamus or sensory cortex injury lose sensory discernment of nociceptive stimuli.
Patients with medial thalamus injury lose emotional experience. Similarly, patients with impaired anterior cingulate cortex (ACC) or insular cortex (IC) retain sensory discernment but do not have painful emotional experiences of nociceptive stimuli.
Thus, the lateral thalamus-sensory cortical pathway may mediate external sensations, such as sensory discrimination, while the medial thalamus-ACC/IC pathway mediates internal sensations, such as anaesthesia to stimuli.
Figure 2: Functional partitioning and convergence of lateral and medial thalamus pathways
Animal Extrasensory and Intrinsic Sensory Behaviors: A Discussion of Various Behavioral Experiments
Reflex behavior produced by nociceptive stimuli in animals is not affected after the brain is removed, indicating that this is a basal reflex behavior mediated by a spinal cord loop that does not involve cognitive and emotional experiences of pain.
Behaviors such as avoidance of uncomfortable temperature chamber, escape and frezing during plantar shock, and jumping in hot plate tests are defensive behaviors of stimuli, and studies have shown that these extraterritorial behaviors also do not involve cognitive and emotional experience of pain.
Animals exhibit paw guarding after being damaged by tissue. In Real-time operant escape assays, animals learn to escape the chamber where nociceptive stimuli are located after recognizing pain. Both of these behaviors require the involvement of brain regions associated with the processing of affective pain, such as ACC. The authors therefore argue that these two external sensory behaviors reflect transient pain perception.
Animals manifest as persistent licking after tissue damage. Studies have shown that this behavior decreases significantly after removal of the brain or destruction of ACC, suggesting that the behavior reflects the internal feeling of persistent pain.
Different primary sensory neurons are involved in exoception and intrinsic sensory behaviors, respectively
Single-cell RNA sequencing classifies DRG neurons into 11 categories of neurons. According to developmental markers, DRG neurons can be classified as Runx1-persistent, Runx1-transient, and Runx1-negative neurons. These three types of neurons functionally mediate exoperceptory behavior, intrinsic sensory behavior, and first pain when subjected to nociceptive stimuli, respectively.
Figure 3: A. Molecular markers, B. developmental markers, and functional classification of DRG neurons
Subnuclears of different lateral paraarm nuclei (lPBN) participate in different behaviors
There are partial functional breakdowns in lPBN: elPBN and dlPBN are involved in generating extrasensory behavior, while slPBN is essential for intrinsic sensory behavior.
Different spinal cord neurons are involved in exoception and intrinsic sensory behaviors, respectively
Tac1+ neurons of the spinal cord are involved in intrinsic sensory behavior. Tac1+ neuronal ablation significantly reduces licking and positional aversion to stimuli without affecting reflex behavior toward nociceptive stimuli.
Interneurons in the spinal cord mediate reflexive behavior towards nociceptive stimuli. Injuries such as SOM+ interneurons significantly reduce reflex behavior.
Inhibition of pain by external sensations in physiological states
Melzack and Wall proposed the famous theory of pain gating in 1965. Studies have shown that the activation of Abeta neurons inhibits the painful behavior caused by the activation of nociceptors.
Inescapable external stimuli can also cause inhibition of pain, such as when animals face existential threats, where fear dominates and pain is suppressed.
In pathological conditions, external and internal sensations work together to promote pain and depression comorbidities
In the pathological state, the activation of Abeta, which transmits tactile information, loses the gating of pain, but instead produces pain.
Nociceptors mediating reflexive behavior do not produce internal sensations of pain in the physiological state, but in the pathological state, they can produce pain and position aversion.
Due to the functional convergence of the medial and lateral thalamus in the ACC/IC brain region, activation of the medial or lateral thalamus in the pathological state may lead to a strong painful emotional experience through the ACC/IC.
Midbrain dopamine neurons can be suppressed by both internally felt pain states and by external threats such as plantar shocks. In pathological conditions, the external and internal sensory systems may work together to lead to inhibition of dopamine neurons in the midbrain, resulting in a depressive comorbidity.
Figure 4: Different loop systems of DRG, spinal cord, lPBN, and forebrain mediate internal and external sensory behaviors, respectively
Implications for pain research
The functional breakdown of internal and external sensations in the somatosensory system has led to the study of pain as follows:
1. Interventions that inhibit external sensory behavior may not be able to suppress the internal sensation of pain. Interventions that do not inhibit external sensory behaviors do not necessarily fail to suppress internal sensory behaviors. Therefore, it is necessary to distinguish between behavioral experiments that reflect reflex behavior, transient pain, and persistent pain.
2. Clinically, a lot of pain is caused by deep organs, such as visceral pain. It is necessary to design and use behavioral experiments that measure external and internal sensations (such as ultrasound sound) in other pain models.
In summary, through the review of the literature, this paper proposes that the somatosensory system can be divided into external sensory system and internal sensory system under physiological conditions. The external and internal sensory systems work together to promote pain and comorbidities in pathological conditions. The current clinical translational challenge of pain research needs to be solved by improving pain models and behavioral approaches.
Original link:
https://doi.org/10.1016/j.neuron.2021.12.015
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Compiled by Hong Chaoli (brainnews creative team)
Reviewer: Simon (Brainnews Editorial Board)