Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0000737 (abdominal pain)
 31,184 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.
 ...
PMID:P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors. 2691 85

Voltage-gated sodium channel Nav1.9 is a threshold channel that regulates action potential firing. Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. Recent studies have demonstrated a monogenic Mendelian link of Nav1.9 to human pain disorders. Gain-of-function variants in Nav1.9, which cause smaller depolarizations of RMP, have been identified in patients with familial episodic pain type 3 (FEPS3) and the more common pain disorder small fiber neuropathy. To explore the phenotypic spectrum of Nav1.9 channelopathy, here we report a new Nav1.9 mutation, N816K, in a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation. Sequencing of further selected pain genes was normal. N816K alters a residue at the N-terminus of loop 2, proximal to the cytoplasmic terminus of transmembrane segment 6 in domain II. Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current. Current-clamp recordings in DRG neurons shows that N816K channels depolarize RMP of small DRG neurons by 7 mV, reduce current threshold of firing an action potential and render DRG neurons hyperexcitable. Taken together these data demonstrate gain-of-function attributes of the newly described N816K mutation at the channel and cellular levels, which are consistent with a pain phenotype in the carrier of this mutation.
 ...
PMID:A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain. 3155 82