Table 2.

the mechanism of cerebral nuclei in comorbidity.

Encephalic region		comorbidity	State	Mechanism	Ref
Amygdala	Amygdala	pain-anxiety	↑	1. decreased global DNA methylation, 2. increased the NMDAR (p-GluN2B, GluN2B, GluN2A, PSD95, Synaptophysin) expressions, 3. increased the AMPAR (GluA1 p-GluA1), 4. increased the microglia activation, 5. increased the proinflammatory mediators (TNF-a, IL−1b) and NF-κB signaling pathway (p65, pIκBa)	58, 35
	CeA	pain-anxiety	↑	1. increased the frequency and the amplitude of mEPSC, 2. increased the GABAergic neurons (increased the PKCδ、SOM neurons).	46, 68
	BLA	pain-anxiety	↑	1. increased CPEB1 expression, 2. shown in Fig10c	8, 16, 19, 25, 31, 33, 65
		pain-depression	↑	increased the c-Fos expression	65
ACC	ACC	pain-anxiety	↑	1. activated the calcium homeostasis moduLator 2 (Calhm2) in pyramidal neurons, 2. shown in the Fig10b	22, 28, 34, 43, 44, 48, 50, 52, 59
	rACC	pain-anxiety	↑	1.increased the neurons activity, 2. increased NMDAR expression (p-GLuN1, p-GluN2A, p-Glun2B)	54
hippocampus	hippocampus	pain-anxiety	↑	increased the BDNF level	14
		pain-cognition	↑	1.increased the IL−1β levels, 2. apoptosis and necroptosis (increased the caspace8, caspsae−3, and Rip3 proteins)	57
		pain-depression	↓	inhibited the PI3K/Akt signaling pathway (decreased of p-PI3K, PI3K, p-Akt, Akt proteins) →neuronal apoptosis (decreased Bcl−2 expression, increased Bax expression)	71
	dorsal hippocampus	pain-cognition	↑	increased the endogenous PPAR ligands (PEA and OEA) levels	41
	vDG、dDG	pain-anxiety	∕	decreased the BDNF levels	8
	dDG	pain-cognition		impaired the neurogenesis
	vCA1	pain-anxiety	↓	pyramidal neurons showed inhibitory responses	67
mPFC		pain-cognition	↑	1. increased the dendritic spine density on pyramidal neurons in the mPFC of male mice but not in female mice, 2. increased the dendritic spine density on interneurons in the mPFC of male and female mice, 3. CFA injection decreased the expression of the glutamate transporter VGlut1 on the soma of mPFC neurons.	56
		pain-anxiety	↑	increased the c-Fos expression	62
	vmPFC	pain-anxiety	↑	enhanced AMPAR trafficking and synaptic transmission	61
	PL	pain-anxiety	↓	decreased the excitatory neurons	15
BNST		pain-anxiety	↑	increased the c-Fos expression	62
LC		pain-anxiety	↑	increased the c-Fos expression	39
		pain-cognition
thalamus		pain-anxiety	↑	increased the NR2B expression	51
NAc		pain-depression	↑	increased the GluA1 expression	17
PAG		pain-depression, pain-anxiety	↑	increased the c-Fos expression	65
RVM			↑