Activity of protein kinase C controls the efficacy of cannabinoid receptor type 1 in the medial prefrontal cortex after neuropathic pain. J Neurophysiol 2025 Dec 01;134(6):2027-2035
Date
11/21/2025Pubmed ID
41269674Pubmed Central ID
PMC12709621DOI
10.1152/jn.00379.2025Scopus ID
2-s2.0-105024777689 (requires institutional sign-in at Scopus site)Abstract
Many patients with chronic pain conditions suffer from depression. In our previous report, we found that afferent noxious inputs after painful nerve injury compromise activity-dependent endocannabinoid (eCB) signaling in the medial prefrontal cortex (mPFC), resulting in depression. Since protein kinase C (PKC) and cAMP/protein kinase A (PKA) pathways can regulate eCB receptor type-1 (CB1R)-mediated synaptic transmission, we explored the possible roles of PKC and PKA in causing reduced eCB signaling in neuropathic pain (spared nerve injury, SNI). Four weeks after SNI, rats developed both depression and hypersensitivity of the plantar skin to punctate mechanical stimulation. Radioligand-based assay of CB1R binding in the harvested mPFC tissue showed no change after SNI in both male and female rats. Slice electrophysiological recordings from the mPFC showed that SNI did not alter the effects of a PKA agonist (forskolin) or blocker (H-89) on evoked inhibitory postsynaptic currents (eIPSCs). However, the PKC blocker chelerythrine (CHEL) fully prevented the inhibitory effect of the CB1R agonist (WIN-55212-2) on eIPSCs, whereas PKC activation with phorbol 12-myristate 13-acetate reversed the reduced effect of WIN-55212-2 on eIPSC and miniature IPSC after SNI. Together, these data suggest that PKC activity controls the efficacy of CB1Rs in mPFC after neuropathic pain.NEW & NOTEWORTHY Our research reveals that protein kinase C (PKC) activity in the medial prefrontal cortex (mPFC) is essential for cannabinoid receptor type 1 (CB1R)-mediated suppression of GABAergic transmission. After neuropathic pain, reduced PKC activity diminishes CB1R efficacy, despite unchanged receptor expression. Restoring PKC activity rescues CB1R function. These findings identify PKC as a critical modulator of endocannabinoid signaling in chronic pain, suggesting new therapeutic targets for pain-associated affective disorders.
Author List
Chao D, Liu Y, Cheng T, Hogan QH, Pan BAuthor
Quinn H. Hogan MD Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCyclic AMP-Dependent Protein Kinases
Endocannabinoids
Hyperalgesia
Male
Neuralgia
Prefrontal Cortex
Protein Kinase C
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
