ABSTRACT
Chromogranin A (CgA) is an acidic protein identified within a large variety of endocrine cells. Colocalized with catecholamines in chromaffin cells, CgA is a prohormone precursor of small biologically active peptides. Vasostatin (CgA 1-76) is the most conserved fragment of CgA and chromogranin A 47-66 peptide (CgA 47-66) possesses potent antimicrobial activities. The aim of this study was to test the hypothesis that CgA 47-66 may be involved in mechanisms modulating nociception. Thus, we used acetic acid (AA) which produces a delayed inflammatory response and episodes of abdominal writhing, a marker of pain, when injected intraperitoneally (i.p.) to rats. Administration (i.p.) of CgA 47-66 induced specific opposite dose-dependent effects depending on concentration. That is, CgA 47-66 below 0.5 mg/kg produced antinociceptive effects, whereas at 2 mg/kg it produced a marked pronociceptive effect. The latter effect was blocked by diltiazem and indomethacin. CgA 47-66-induced antinociceptive effects on AA-induced responses were reversed when the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF 9-41 was i.p. injected to animals prior to AA and CgA 47-66 administration. The administration of i.p. calcitonin gene-related peptide (CGRP) or substance P (SP) evoked dose-dependent abdominal writhing; this effect was abolished when CgA 47-66 was injected. The present data suggest, for the first time, that a fragment of CgA, CgA 47-66, possesses potent antinociceptive effects at low doses. Although the mechanism triggered by this peptide is unknown, CRF receptors are likely to be involved.
Subject(s)
Acetic Acid/toxicity , Chromogranins/administration & dosage , Pain/chemically induced , Pain/drug therapy , Peptide Fragments/administration & dosage , Animals , Calcitonin Gene-Related Peptide/administration & dosage , Cardiovascular Agents , Chromogranin A , Corticotropin-Releasing Hormone/administration & dosage , Diltiazem , Dose-Response Relationship, Drug , Indomethacin/administration & dosage , Male , Pain/metabolism , Pain Management , Rats , Rats, Wistar , Receptors, Corticotropin-Releasing Hormone/metabolism , Substance P/administration & dosageABSTRACT
The effect of graded doses (10(-10)-10(8) M) of highly purified bovine parathyroid secretory protein-I (SP-I; chromogranin-A) or synthetic porcine pancreastatin on glucose-stimulated insulin release in the perfused rat pancreas was examined. SP-I (10(-9) M) inhibited the first phase of glucose-stimulated insulin release, and 10(-8) M SP-I inhibited both the first and second phases of glucose-stimulated insulin release; 10(-10) M SP-I was inactive. In comparison, pancreastatin at 10(-10) M inhibited the first phase of insulin release, and at 10(-9) and 10(-8) M, pancreastatin inhibited both phases of insulin release. The inhibition by SP-I was achieved at concentrations that normally exist in the general circulation of man. These and other data suggest that circulating SP-I plays a physiological role in the regulation of insulin secretion.
