Hypersensitivity of Prelimbic Cortex Neurons Contributes to Aggravated Nociceptive Responses in Rats With Experience of Chronic Inflammatory Pain

Abstract

Previous experience of chronic pain causes enhanced responses to upcoming noxious events in both humans and animals, but the underlying mechanisms remain unclear. In the present study, we found that rats with complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain experience exhibited aggravated pain responses to later formalin test. Enhanced neuronal activation upon formalin assaults and increased phosphorylated cAMP-response element binding protein (CREB) were observed in the prelimbic cortex (PL) of rats with chronic inflammatory pain experience, and inhibiting PL neuronal activities reversed the aggravated pain. Inflammatory pain experience induced persistent p38 mitogen-activated protein kinase (MAPK; p38) but not extracellular regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) hyperphosphorylation in the PL. Inhibiting the p38 phosphorylation in PL reversed the aggravated nociceptive responses to formalin test and down-regulated enhanced phosphorylated CREB in the PL. Chemogenetics identified PL–periaqueductal gray (PAG) but not PL–nucleus accumbens (NAc) as a key pathway in inducing the aggravated formalin pain. Our results demonstrate that persistent hyperphosphorylation of p38 in the PL underlies aggravated nociceptive responses in rats with chronic inflammatory pain experience.

Gait Assessment of Pain and Analgesics: Comparison of the DigiGait™ and CatWalk™ Gait Imaging Systems

“…Intraplantar injection of CFA induces instant thermal and mechanical hyperalgesia within 1 h; this hypersensitivity lasts for two weeks and then gradually subsides [ 24 – 26 ]. Thus, we performed sensory and motor analyses at 7 and 9 dpi, when the models showed stable mechanical allodynia.…”

Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression

“…In neuropathic pain models, excitability of layer 5 pyramidal neurons was reduced in the prelimbic cortex ( Radzicki et al, 2017 ; Cheriyan and Sheets, 2018 ), but not infralimbic cortex ( Cheriyan and Sheets, 2018 ). In contrast, the activation of prelimbic neurons was increased in an inflammatory pain model ( Dale et al, 2018 ; Fan et al, 2018 ), with increased excitability of layer 5 pyramidal neurons ( Wu et al, 2016 ). Interestingly, intrinsic excitability was reduced in the layer 2/3 pyramidal neurons in the same inflammatory pain model ( Wang G.Q.…”

“…The administration of an HCN channel blocker decreased neuronal excitability in the slice condition, and reduced cold but not mechanical allodynia in vivo . Fan et al (2018) showed that hyperresponsive prelimbic neurons are critically involved in enhanced behavioral responses to noxious stimuli after chronic pain. The previous experience of CFA-induced chronic pain enhanced prelimbic neuronal activation following formalin assaults, and inhibiting prelimbic activity reversed aggravated formalin pain.…”

Role of the Prefrontal Cortex in Pain Processing

“…In one study, rats with unilateral infraorbital nerve chronic constriction injury show bilateral trigeminal dynamic mechanical allodynia, and bilateral upregulation of pERK-1/2 in the ventro-mPFC 2 weeks after nerve injury, suggesting that these changes may contribute to altered pain perceptions [ 114 ]. Another study, however, found that inflammatory pain induces persistent p38 mitogen-activated protein kinase (P38) but not ERK or c-Jun N-terminal kinase hyperphosphorylation in the prelimbic cortex [ 115 ].…”