Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain.
Collectively, the results in this study indicated nerve injury diminishes spinal Hes1-dependent suppression of CDK9-dependent RNAPII phosphorylation on the mGluR5 promoter that possibly enhances mGluR5 transcription/expression for neuropathic pain development.
Interestingly, 2% moringin cream treatment was found to modulate the expression of voltage-gated ion channels (results focused on P2X7, Nav 1.7, Nav 1.8 KV4.2, and α2δ-1) as well as metabotropic glutamate receptors (mGluR5 and xCT) involved in neuropathic pain initiation and maintenance.
A pharmacological blockade of upregulated mGluR5 in the PrL ameliorated the negative symptoms including tactile hypersensitivity and depressive-like behavior, which relieved the subjects from the unpleasant state of chronic neuropathic pain condition.
Furthermore, the expressions of metabotropic glutamate receptor (mGluR1) and mGluR5, which play a key role in central sensitization and neuropathic pain, and H3 acetylation levels at Grm1/5 (encoding mGluR1/5) promoter regions were increased in diabetic neuropathic pain rats.
Our findings suggest that paclitaxel-induced painful neuropathy is associated with increased presynaptic mGluR5 activity at the spinal cord level, which serves as upstream signaling for PKC-mediated tonic activation of NMDARs. mGluR5 is therefore a promising target for reducing chemotherapy-induced neuropathic pain.
These findings suggest that increased mGluR5 expression on primary afferent neurons contributes to increased glutamatergic input to spinal dorsal horn neurons and nociceptive transmission in diabetic neuropathic pain.