Pain
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A large body of evidence indicates how pain affects motor control, yet the way the motor system influences pain perception remains unclear. We present 2 experiments that investigated sensory attenuation of pain implementing a 2-alternative forced choice paradigm. Particularly, healthy participants received painful stimuli on a moving and nonmoving hand during the execution or the preparation of reaching motor actions. ⋯ Together these findings indicate that executing, but not preparing, a motor action affects pain processing in that body part. No significant associations were found between sensory attenuation indices and inhibitory control abilities or pain catastrophizing, vigilance and rumination. These results provide insight into the inhibitory effects of motor actions on pain processing, suggesting that pain perception is a dynamic experience susceptible to individuals' actions in the environment.
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Activation of transient receptor potential ankyrin 1 (TRPA1) channels by both environmental irritants and endogenous inflammatory mediators leads to excitation of the nerve endings, resulting in acute sensation of pain, itch, or chronic neurogenic inflammation. As such, TRPA1 channels are actively pursued as therapeutic targets for various pathological nociception and pain disorders. We uncovered that exon 27 of human TRPA1 (hTRPA1) could be alternatively spliced into hTRPA1_27A and hTRPA1_27B splice variants. ⋯ Knockdown of SRSF1, mutation within exonic splicing enhancer, or masking SRSF1 binding with antisense oligonucleotides promoted alternative splicing within exon 27. Finally, antisense oligonucleotides-induced alternative splicing produced transcript and protein variants that could be functionally determined as diminished endogenous TRPA1 activity in human Schwann cell-line SNF96.2 and hiPSCs-derived sensory neurons. The outcome of the work could potentially offer a novel therapeutic strategy for treating pain by targeting alternative splicing of hTRPA1.
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The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. ⋯ By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.