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. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of
m6A in ten-eleven translocation methylcytosine
dioxygenases 1 (Tet1)
mRNA and TET1
protein in the spinal cord, leading to production of
pain hypersensitivity. 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.