Table.

Mechanism of Action and Receptor Targeting of Future Drugs for the Management of Visceral Hypersensitivity

Source	Agents as future drugs	Cell/ receptor targets	Therapeutic effects in managing VH	References
Chemical	5-aminosalicylic acid	Intestinal immune cells	↓Inflammation and pain perception	19, 49, 50
	A-803467	Selective Nav1.8 sodium channel blocker	↓Mechanical allodynia and thermal hyperalgesia	90
	Alosetron	5-HT3 receptor antagonist	↑Volume thresholds, ↓Colonic compliance, ↓Emotional motor system of brain activity and modulation of the gut sensitivity	60, 61
	Ambroxol	Na+channel blocker	↓Inflammatory pain	91
	Asimadoline	κ-opioid receptor agonist	↓Pain sensation, ↓Hyperalgesia in functional dyspepsia	78–80
	AYPGKF-NH2	PAR4 agonist peptide	↓Visceromotor response to colorectal distension	102, 103
	Capsazepine	TRPV1 receptor antagonist	↓Inflammation and visceral pain	67, 72
	CNQX	Non-selective glutamate AMPA receptor antagonist	↓Visceral perception induced by substance P	96
	Ebastine and fexofenadine	Histamine-1-receptor antagonists	↓Stress associated VH	54
	Eluxadoline	μ-opioid receptor agonist and δ-opioid receptor antagonist	↑Pain threshold	80, 81
	Fedotozine	κ-opioid receptor agonist	↓Pain sensation, ↓Volume or pressure stimuli perception	78–80
	K252A	TrkA antagonist	↓VH in colorectal distension	84
	Ketotifen	Histamine-1-receptor antagonist and mast cell stabilizer	↓Hyperalgesia, discomfort and abdominal pain	56
	Lidocaine	Voltage gated Na+ channels blocker	↑Pain threshold, ↓Rectal hypersensitivity	89
	Mibefradil, ethosuximide, and NP078585	Calcium channel antagonists	↓Butyrate-induced VH	88
	Nepadutant and saredutant	NK2 receptor antagonists	Modulation the colorectal hypersensitivity to distension	74–77
	PF-03550096	Selective CB2 receptor agonist	↓Visceral hyperalgesia	101
	Propranolol	β-adrenergic receptor antagonist	↓Heterotypical intermittent stress-induced VH	92, 93
	RQ-00202730	Selective CB2 receptor agonist	↓Visceral hyperalgesia	100
	SB366791	TRPV1 receptor antagonist	↓Thermal hyperalgesia	71
	SR-140333 and MEN-10930	Selective NK1 receptor antagonists	↓Inflammatory associated hyperalgesia	73–75
	SR-142801	Selective NK3 receptor antagonist	↓Inflammatory associated VH	75–77
	TAK-242	Specific TLR4 receptor antagonist	↓Chronic stress-induced VH	53
	Tegaserod	Partial 5-HT4 receptor agonist	↓Sensitivity to rectal distension, Improved visceral sensation	62–64
Natural	Berberine	Involvement of nitric oxide synthetase	↓Abdominal withdrawal reflex score to colorectal distention, ↓Defecation times, Improvement of stool consistency	138
	Curcumin	Involvement of TRPV1 and 5-HT1a receptors, Modulation of BDNF, 5-HT and pCREB	↓Visceromotor response to colorectal distension, Modulation of depressive behavior in IBS	125, 126
	Dicentrine	α-adrenoceptor antagonist, Involvement of TRPA1 receptors	↓Visceral pain perception	130, 131
	Ginseng saponins	5-HT3a receptor blocker	Antinociceptive effect in VH	141
	Probiotics	Gut microflora	↓Intestinal permeability and contractile response of colonic smooth muscle, ↓VH symptoms of post-infectious IBS, Regulation of pain transmission mediators and inflammatory cytokines	41, 113–115
	Tetrahydropalmatine	Not identified	↑Pain threshold, ↓Primary hyperalgesia due to thermal and mechanical stimuli, Antinociceptive effect	143, 145

VH, visceral hypersensitivity; 5-HT, serotonin; PAR, protease-activated receptor; TRPV1, transient receptor potential vanilloid type I; CNQX, 6-cyano-7-nitro-quinoxaline-2,3-dione disodium; AMPA, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; TrkA, tyrosine receptor kinase A; NK, neurokinin; CB, canna-binoid; TLR, toll like receptor; BDNF, brain derived neurotrophic factor; pCREB, phosphorylated cAMP-response element binding protein; IBS, irritable bowel syndrome; TRPA, transient receptor potential cation channel.