Background & Aims

Sngception is a unique somatosensory function to sense tissue acidosis and/or mechanical stimuli, which is distinguishable from nociception[1, 2]. The corresponding perception is sng (soreness). While the feature of pain response is suffering, sng responses can be either suffering or relief by massage or stretching. Thus, active reliving maneuvers are unique features of sng behaviors that are distinct from pain behaviors featured with avoiding and/or guarding tendency of reduced movement. However, the molecular and neurobiological basis of sngception remains unknown, although acid-sensing ion channels (ASICs) are hypothetically engaged in acid-sensation, therefore sngception[3]. A major technical challenge to probe sngception is the lack of behavioral assessment to distinguish sng-like responses from pain-like responses in animal models. Here we aim to explore the sng-like behaviors in a mouse model of acetic acid (AA) induced stretch response.

Methods

Traditionally mechanical reflexes like von Frey assay or muscle withdrawal threshold are used to measure tissue hypersensitivity, which responses may commonly be shared by both sng and pain. Reduction of spontaneous discrete behaviors is another method commonly used as nociceptive metrics. In contrast, we hypothesize active relieving maneuvers can be a measure for sng-like response in animal models. We exploited the AA-induced stretch behavior to understand sngception in mice. We developed a method from 2-D surface projection changes to measure the spontaneous behavior in a continuum to gauge sng-like responses via the general dynamism of movements and pain-like responses from restricted movements with sub-second precision, a behavior exclusive to pain. We used various doses of different analgesics to understand their sensitivity to these behaviors. Further, we manipulated different proton-sensitive and pro-nociceptive ion channels to re-visit their roles in sngception and nociception.

Results

We found that sng-like stretch and pain-like restricted movement behaviors can be independently triggered via the same or different stimuli. Using intraperitoneal AA stimulation, we dissected an early onset of sng-like stretching behavior, distinguishable from late-onset pain-like restricted movements. Temporal changes of sng-like and pain-like behaviors are consistent with a late onset increase in the mouse grimace scale. Further, known analgesics like diclofenac and ibuprofen affected these behaviors with different sensitivity. As for the molecular determinants, proprioceptor-specific knockouts of ASIC3 and ASIC1b showed an increase in sng-like stretching behavior without affecting the pain-like phenotype or overall movement patterns. Surprisingly, we found knockout of ASIC1a reduced sng-like behaviors without affecting pain-like ones. Moreover, knockout of the pronociceptive Nav1.8 only alleviated pain-like restricted movements, where stretching behavior remained unaffected.

Conclusions

Our results indicate that sng-like and pain-like behaviors can be dissected independently in mice. These two behaviors are governed by distinct molecular mechanisms, where ASIC channels govern sng-like behavior and pro-nociceptive Nav1.8 ion channels dictate pain-like behavioral outcomes. Moreover, conditional knockout studies suggest sngceptive behaviors are of proprioceptor origin.

References

1.Hsu, W.H., et al., Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia. European journal of pain, 2022. 26(2): p. 445-462.
2.Chiu, H.-Y., et al., Soreness: An Ignored Clinical Symptom of Chronic Low-Back Pain Affects Mental Health. Available at SSRN 3426081, 2019.
3.Lin, J.-H., et al., Sensing acidosis: nociception or sngception? Journal of biomedical science, 2018. 25(1): p. 1-8.

Presenting Author

Mohammad Tauhid Siddiki Tomal

Poster Authors

Md Tauhid Siddiki Tomal

BSc

Institute of Biomedical Sciences, Academia Sinica, Taiwan

Lead Author

E-mail

Cheng-Han Lee

Institute of Biomedical Sciences, Academia Sinica, Taiwan

Lead Author

E-mail

Wei-Hsin Sun

National Yang Ming Chiao Tung University

Lead Author

E-mail

Chih-Cheng Chen

IBMS, Academia Sinica

Lead Author

E-mail

Topics

  • Models: Visceral