A systematic review of the pain-related emotional and cognitive impairments in chronic inflammatory pain induced by CFA injection and its mechanism

Emotional and cognitive impairments are comorbidities commonly associated with chronic inflammatory pain. To summarize the rules and mechanisms of comorbidities in a complete Freund's adjuvant (CFA)-induced pain model, we conducted a systematic review of 66 experimental studies identified in a search of three databases (PubMed, Web of Science, and ScienceDirect). Anxiety-like behaviors developed at 1- or 3-days post-CFA induction but also appeared between 2- and 4 weeks post-induction. Pain aversion, pain depression, and cognitive impairments were primarily observed within 2 weeks, 4 weeks, and 2-4 weeks post-CFA injection, respectively. The potential mechanisms underlying the comorbidities between pain and anxiety predominantly involved heightened neuronal excitability, enhanced excitatory synaptic transmission, and neuroinflammation of anterior cingulate cortex (ACC) and amygdala. The primary somatosensory cortex (S1)Glu-*caudal dorsolateral striatum (cDLS)GABA, medial septum (MS)CHAT-*rACC, rACCGlu-*thalamus, parabrachial nucleus (PBN)-*central nucleus amygdala (CeA), mediodorsal thalamus (MD)-*basolateral amygdala (BLA), insular cortex (IC)-*BLA and anteromedial thalamus nucleus (AM)CaMKII-*midcingulate cortex (MCC)CaMKII pathways are enhanced in the pain-anxiety comorbidity. The ventral hippocampal CA1 (vCA1)-*BLA and BLA-*CeA pathways were decreased in the pain-anxiety comorbidity. The BLA-*ACC pathway was enhanced in the pain-depression comorbidity. The infralimbic cortex (IL)-*locus coeruleus (LC) pathway was enhanced whereas the vCA1-*IL pathway was decreased, in the pain-cognition comorbidity. Inflammation/neuroinflammation, oxidative stress, apoptosis, ferroptosis, gut-brain axis dysfunction, and gut microbiota dysbiosis also contribute to these comorbidities.