dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors

Abstract

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we showed that lesions of the dmPFC induced an algesic and anxious state. By using multiple tracing methods including rabies-based transsynaptic tracing method, an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG) was outlined. Specific activation of the dmPFC-vlPAG neural pathway by an optogenetic manipulation, produced analgesic and anxiolytic effects in a chronic pain mice model. Inhibitory neurons in the dmPFC were specifically activated by using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of GABAAR or mGluR1 were applied to the dmPFC, which produced analgesic and anxiolytic effects. In summary, the present results suggest that the dmPFC-vlPAG neural pathway might participate in the maintenance of pain thresholds and anxiolytic behaviors under normal conditions, while silencing or suppressing the dmPFC-vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.

Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

“…Moreover, activation of the PL-PAG pathway relieves hyperalgesia in tibial nerve transection mouse models ( Drake et al, 2021 ). Another study ( Yin et al, 2020 ) showed that the dorsal mPFC -ventrolateral periaqueductal gray (including the rACC-vlPAG and PL-vlPAG pathways) glutamatergic pathway positively regulates 5-HT neurons in the rostral ventromedial medulla, participating in a descending pain modulatory system from the cortex to the spinal cord. Specific activation of the dmPFC-vlPAG pathway by an optogenetic technique produced analgesic and anxiolytic effects in a common peroneal nerve ligation model.…”

Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients

“…Impaired defensive behaviour is a main psychopathological root of anxiety disorders and, as we discussed above, PAG–dmPFC connectivity plays a pivotal role in contextual fear discrimination 56 , 62 . In a recent animal study, Yin et al demonstrated that the activation of excitatory descending pathway from dmPFC to vlPAG has analgesic and antianxiety effects 72 . Our results might suggest that tryptophan and its metabolites actively modulate the functional coupling of PAG and the dmPFC/dlPFC.…”

MHCII Contributes to Bone Cancer Pain via Activating the NLRP3 Inflammasome in Microglia of the Medial Prefrontal Cortex

“…Our result showed that the expression of MHCII was signi cantly upregulated in multiple brain regions (Figure S1), including mPFC which is a central hub for the comorbidity of chronic pain, depression and anxiety [10,44]. It also has been reported that mPFC participates in pain by connecting with PAG [45]. In the meantime, it has been suggested that in the mPFC, microglia activation and subsequent pro-in ammatory responses play a crucial role in the development of neuropathic pain [11,46].…”