TABLE 2.

Inflammatory response regarding different types of treatments.

Pain models investigating depression
References		Pain model	Therapeutic intervention	After treatment
				Painful behavior	Depressive-like behavior	Inflammatory effects
Birmann et al., 2019		PSNL	3-(4-Chlorophenylselany)-1-methyl-1H-indole	↑ Thermal nociceptive threshold using the hot plate test	↓ Immobility in the FST	↓ ROS and lipid peroxidation in the cortex and hippocampus
				↑ Mechanical nociceptive threshold using the von Frey test	↑ Grooming in the splash test	↓ Costicosterone in plasma
Zhang et al., 2016		CFA	Acute dose of ketamine	↑ Thermal nociceptive threshold using the hot plate test	↓ Immobility in the FST	↓ IL-6 and IL-1β in the hippocampus
				↑ Mechanical nociceptive threshold using the von Frey and paw pressure tests	↑ Sucrose preference	↓ Indoleamine 2,3-dioxygenase and kynurenine in the hippocampus
Vachon et al., 2013		SNI	Environmental enrichment	↑ Thermal nociceptive threshold using the hot plate and acetone tests	No change in time in close-arms in the EPM	↓ SP and CGRP in the lumbar spinal cord
				↑ Mechanical nociceptive threshold using the von Frey test	No change in time in the tail suspension
Murad and Ayuob, 2015		CCI	Fluoxetine	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ TNF-α, IL-6, MCP-1 in plasma
						↑ IL-10 in plasma
						↓ GFAP expression in the spinal cord
						↓ Myelin degeneration and leukocyte infiltration
			Pioglitazone	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ TNF-a, IL-6, MCP-1 in plasma
						↑ IL-10 in plasma
				↑ Mechanical nociceptive threshold using the von Frey test		↓ GFAP expression in the spinal cord
						↓ Myelin degeneration and leukocyte infiltration
			Metformin	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ TNF-α, IL-6, MCP-1 in plasma
						↑ IL-10 in plasma
				↑ Mechanical nociceptive threshold using the von Frey test		↓↓ GFAP expression in the spinal cord
						↓ Myelin degeneration and leukocyte infiltration
			Fluoxetine + pioglitazone	↑ Thermal nociceptive threshold using the Hargreaves test	↓↓ Immobility in the FST	↓ TNF-α, IL-6, MCP-1 in plasma
						↑ IL-10 in plasma
				↑ Mechanical nociceptive threshold using the von Frey test		↓↓ GFAP expression in the spinal cord
						↓↑ Myelin degeneration and leukocyte infiltration
			Fluoxetine + metformin	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ TNF-α, IL-6, MCP-1 in plasma
						↑ IL-10 in plasma
				↑ Mechanical nociceptive threshold using the von Frey test		↓↓ GFAP expression in the spinal cord
						↓↓ Myelin degeneration and leukocyte infiltration
Cai et al., 2019		LDH	Fluoxetine	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ TNF-α in the hippocampus
				↑ Mechanical nociceptive threshold using the von Frey test	↑ Sucrose preference
Fang et al., 2019		SNI	IRF8 siRNA	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ IRF8 in the spinal cord
					↑ Sucrose preference	↓ BDNF in the NAc
			Pulsed frequency	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ IRF8 in the spinal cord
					↑ Sucrose preference	↓ BDNF in the NAc
Redivo et al., 2016		STZ	Fish oil	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST (modified)	↑ BDNF in the hippocampus and PFC
Li et al., 2017		SCI	ZBD-2	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ Iba-1 and GFAP expression in the hippocampus and spinal cord
				↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the tail suspension	↑ BDNF in the hippocampus and spinal cord
						↓ Costicosterone in plasma
Shen et al., 2018		STZ	Palmatine	↑ Thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ GFAP and P2X7 expression in the hippocampus
				↑ Mechanical nociceptive threshold using the von Frey test	↑ Sucrose preference	↓ TNF-α and IL-1β in the hippocampus
Hisaoka-Nakashima et al., 2019		PSNL	GZA (anti HMGB-1)	Not measure	↓ Immobility in the FST	↓ Iba-1 expression (activation) in the PFC
					↑Social interaction
					↓ Novelty suppressed feeding
Li et al., 2019		CCI	AcYVAD-CMK (caspase-1 inhibitor)	No change in thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	Not measure
				No change in mechanical nociceptive threshold using the von Frey test	↑ Climbing in the FST No change in the EPM
			2-AP (2-aminopurine - PKR inhibitor)	No change in thermal nociceptive threshold using the Hargreaves test	↓ Immobility in the FST	↓ Inflamassome (NLRP1) and caspase-1 expression in the hippocampus
					No change in mechanical nociceptive threshold using the von Frey test	↑ Climbing in the FST No change in the EPM
Pan et al., 2018		SNI	Ketamine	No change in mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↑ BDNF in the PFC
						↑ NL1 and ↓ NL2 in the PFC
						↑ BDNF in the ACC
						No change in NL1 and NL2 in the ACC
						↑ BDNF in the hippocampus
						No change in NL1 and ↑ NL2 in the hippocampus
Brüning et al., 2015		PSNL	acute (m-CF3-PhSe)2	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	No change in pro-inflammatory cytokines in serum, cortex and hippocampus
						↓ COX2 and NF-κB in the cortex
						↑ BDNF in cortex
						↓ COX2 and no change in NF-κB in the cortex
						↑ BDNF in the hippocampus
						No change in ACTH and corticosterone
			subchronic (m-CF3-PhSe)2	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ IL-1β, IL-6, TNF-α, IFN-γ and ↑ IL-10 in serum
						↓ IL-1β, IL-6, TNF-α, IFN-γ in the cortex and hippocampus
						↓ COX2 and NF-κB in the cortex
						↑ BDNF in cortex
						↓ COX2 and no change in NF-κB in the hippocampus
						↑ BDNF in the hippocampus
						↓ ACTH and corticosterone in serum
Zhou et al., 2015		SNI	IL-1RA	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ Ido-1 and IL-1β in liver
			Ido -/-	No change in mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST ↑ Social interaction	Not measure
Laumet et al., 2018		SNI	IL-1RA inhibitor	No change in mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	Not measure
			Ro61-8048 (KMO inhibitor)	No change in mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	Not measure
Hu et al., 2017		SNL	Triptolide	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ Iba-1 and p38 expression in the hippocampus
					↑ Sucrose preference	↓ IL-1β, TNF-α and ↑ IL-10 in the hippocampus
			Fluoxetine	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ Iba-1 and p38 expression in the hippocampus
					↑ Sucrose preference	No change in IL-1β and TNF-α; ↑ IL-10 in the hippocampus
			Fluoxetine + triptolide	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↓ Iba-1 and p38 expression in the hippocampus
					↑ Sucrose preference	↓ IL-1β, TNF-α and ↑ IL-10 in the hippocampus
Moschetti et al., 2019		Vincristine	PC1 (PK-Rs antagonist)	↑ Thermal nociceptive threshold using the plantar and acetone tests	No difference in the FST and sucrose preference	↓ IL-1β, TNF-α, IL-6, TLR4, CD68 and CD11b and ↑ IL-10 in the DRG
				↑ Mechanical nociceptive threshold using the von Frey test		↓ IL-1β, TNF-α, TLR4, CD68 and CD11b and ↑ GFAP in the spinal cord
Aguilar-Ávila et al., 2019		STZ	β-Caryophyllene	↑ Thermal nociceptive threshold using the hot-plate test	↓ Immobility in the FST	↓ SP, IL-1β, TNF-α and IL-6 in serum
				↑ Mechanical nociceptive threshold using the von Frey test and SMALGO®	↓ Immobility in the tail suspension ↓ Murbles touched
Arora and Chopra, 2013		Reserpine	Berberine	↑ Thermal nociceptive threshold using the tail-immersion test	↓ Immobility in the FST	↓ SP in the cortex and hippocampus
				↑ Mechanical nociceptive threshold using the paw pressure and von Frey tests		↓ Lipid peroxide, non-protein thiols, superoxide dismutase and nitrite levels in the cortex
						↓ Lipid peroxide, non-protein thiols, superoxide dismutase and nitrite levels in the hippocampus
Zong et al., 2018		SNT	Rosiglitazone	↑ Mechanical nociceptive threshold using the von Frey test	↓ Immobility in the FST	↑ BDNF in HC
					↑ Sucrose preference	↓ TNF-α, IL-1β, SOD e MDA in the hippocampus
					↓ Immobility in the tail suspension
			Morphine	↑ Mechanical nociceptive threshold using the von Frey test	No change in immobility in the FST	Not measure
					No change in the sucrose preference
					No change in immobility in the tail suspension
			Rosiglitazone + Compound C (AMPK inhibitor)	No change in mechanical nociceptive threshold using the von Frey test	No change in immobility in the FST	↓ TNF-α, IL-1β, SOD e MDA in the hippocampus
					No change in the sucrose preference
					No change in immobility in the tail suspension
			Rosiglitazone + 3-methyladenine (3-MA - autophagic antagonist)	No change in mechanical nociceptive threshold using the von Frey test	No change in immobility in the FST	No change in TNF-a, IL-1b, SOD e MDA in the hippocampus
					No change in the sucrose preference
					No change in immobility in the tail suspension
Depressive-like models investigating pain
References		Depressive-like model	Therapeutic intervention	After treatment
				Painful behavior	Depressive-like behavior	Inflammatory effects
Sousa et al., 2018		Acute stress restriction	α-(phenylselanyl) acetophenone (PSAP)	↑ Thermal nociceptive threshold using the hot plate test	↓ Immobility in the FST	↓ Lipid peroxidation, reactive species, nitrite and nitrate in the cortex
					↑ Sucrose preference	↓ Lipid peroxidation, reactive species, nitrite and nitrate in the hippocampus
				↑ Mechanical nociceptive threshold using the von Frey	↑ Time spent in open arms in the EPM	↓ Costicosterone in plasma
					↓ Murbles buried
			Imipramine	↑ Thermal nociceptive threshold using the hot plate test	↓ Immobility in the FST	↓ Lipid peroxidation, reactive species, nitrite and nitrate in the cortex
					↑ Sucrose preference	↓ Lipid peroxidation, reactive species, nitrite and nitrate in the hippocampus
				↑ Mechanical nociceptive threshold using the von Frey test	↑ Time spent in open arms in the EPM	↓ Costicosterone in plasma
					↓ Murbles buried
Pain and depressive-like models
References	Pain model	Depressive-like model	Therapeutic intervention	After treatment
				Painful behavior	Depressive-like behavior	Inflammatory effects
Burke et al., 2015	SNL	OB	Amitriptyline	No change in thermal nociceptive threshold using the Hargreaves and acetone tests	↓ Noxious avoidance behavior	↓ GFAP expression in the PFC
				↑ Mechanical nociceptive threshold using the von Frey test		↓ IL-10 and CCL5 and ↑ TNF-α in the PFC
Rivat et al., 2010	Formaline	Social defeat	Chlordiazepoxide	No change in mechanical nociceptive threshold using the von Frey and paw pressure tests	↑ Time spent in the open arms in the EPM	↓ iNOS and COX2 in the PFC
				No change in nociceptive threshold by Dubusson and Dennis score
			Aspirine	↑ Mechanical nociceptive threshold using the von Frey and paw pressure tests	No change in the EPM	↓ iNOS and COX2 in the PFC
				↑ Nociceptive threshold by Dubusson and Dennis score
			CCK2 antagonist (i.p)	↑ Mechanical nociceptive threshold using the von Frey and paw pressure tests	↑ Time spent in the open arms in the EPM	↓ iNOS and COX2 in the PFC
				↑ Nociceptive threshold by Dubusson and Dennis score
			CCK2 antagonist (RVM injection)	↑ Mechanical nociceptive threshold using the von Frey and paw pressure tests	Not measure	Not measure
				↑ Nociceptive threshold by Dubusson and Dennis score
Burke et al., 2014	SNL	OB	Mynocyclin	↑ Thermal nociceptive threshold using the acetone test	Locomotor hyperactivity in the OFT	↑ IL-1β, IL-6 and SOCS3 in the PFC
				↑ Mechanical nociceptive threshold using the von Frey test		↑ IL-10 and MRC2 in the PFC
Clinical data
References		Diagnosis	Therapeutic intervention	After treatment
				Painful behavior	Depressive-like behavior	Inflammatory effects
Atkinson et al., 1986		Chronic pain with coexisting major depression	Dexamethasone	Not measure	Not measure	Non-suppressed cortisone levels
Wingenfeld et al., 2010		Fibromyalgia	DEX and DST	Pain Experience Scale Heat and pressure Pain	SCID-II BDI	MDD patients ↑ cortisol before or after DEX
						Patients with fibromyalgia + MDD ↑ cortisol
						↑ depression x ↑ sensitivity to pressure pain
France and Krishnan, 1985		Chronic low back	DEX and DST	Not measure	DSM- III	↑ cortisol in chronic back patients with major depression (related with depressive symptoms)

BDI-II, Beck Depression Inventory; BDNF, brain-derived neurotrophic factor; CCI, chronic constriction injury; CD11b, cluster of differentiation 11b; CD68, cluster of differentiation 68; CFA, complete Freund’s adjuvant; CGRP, calcitonin gene related peptide; COX2, cyclooxygenase 2; DEX, dexamethasone; DSM-III, Diagnostic and Statistical Manual of Mental Disorders III; DST, suppression test; EPM, elevated plus maze; FST, forced swimming test; GFAP, glial fibrillary acidic protein; HC, hippocampus; Iba-1, ionized calcium-binding adapter molecule 1; IL, interleukin; IL-1RA, interleukin 1 receptor antagonist; IRF8, interferon regulatory factor 8; Ido, indoleamine 2,3, dioxygenase inhibitor; iNOS, inducible nitric oxide synthase; LDH, lumbar disk herniation; MCP1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MDD, major depressive disorder; MRC2, mannose receptor C type 2; NF-κB, factor nuclear kappa B; NL1, neuroligins 1; NL2, neuroligins 2; NLRP-1 inflamassome, Nod-like receptor protein (NLRP)-1 inflammasome; OB, olfactory bulbectomy; P2X7, purinergic receptor P2X7; p38, p38 mitogen-activated protein kinases – MAPKs; PC1, triazine guanidine derivative selective; PFC, prefrontal cortex; PSNL, partial spinal nerve ligation; SCI, spinal cord injury; SCID-II, Structured Clinical Interview for DSM-IV Axis II Personality Disorders; siRNA, small interfering RNA; SNI, spared nerve injury; SNL, spinal nerve ligation; SNT, sciatic nerve transaction; SOCS3, suppressor of cytokine signaling 3; SOD, superoxide dismutase; SP, substance P; STZ, streptozotocin; TNF-α, tumor necrosis factor alfa.