Some evidence has suggested the existence and differential distribution of neuropeptide Y (NPY) receptor subtypes in the mammalian brain (Dumont et al., 1990; Aicher et al., 1991). We now report on the extensive characterization and visualization of at least two classes of NPY receptor sites using a highly selective Y1 analog, [Leu31,Pro34]-NPY or [Pro34]-NPY, and a relatively specific Y2 competitor, NPY13-36. Autoradiographic studies using 125I-peptide YY (125I-PYY) clearly reveal that the Y1 receptor subtype is most abundant in various cortical areas, the dentate gyrus of the hippocampal formation, the claustrum, and the reuniens nucleus of the thalamus. In most other regions, 125I-PYY binding is potently inhibited by increasing concentrations of either NPY2-36 or NPY13-36, suggesting a Y2-like profile. Furthermore, binding assays using homogenates from discrete brain regions clearly demonstrate that various NPY fragments and analogs compete for 125I-PYY labeling with profiles indicative of heterogeneity of NPY receptor subtypes, even in the presence of a selective Y1 blocker. Thus, it is likely that, in addition to the Y1 receptor, which is particularly concentrated in cortical areas, the rat brain is enriched with a receptor class (Y2) that can exist under high- or low-affinity states or with additional receptor subtypes that are recognized by 125I-PYY. These findings cannot be explained by the existence of the very recently reported Y3 receptor subtype, since PYY does not possess significant affinity to this site (Grundemar et al., 1991). Further experiments are currently in progress to determine the nature and functional significance of each of these NPY/PYY receptor sites.
The role of calcitonin gene-related peptide (CGRP) on colorectal distension-induced visceral pain was investigated in conscious rats. Intracolonic administration of acetic acid (0.6%) resulted in a significantly increased number of abdominal contractions in response to colorectal balloon distension from 5.8 +/- 1.2 in controls to 16.6 +/- 1.0 in acetic acid-treated animals (P < 0.05), evidencing sensitization of visceral afferent pathways and subsequently visceral hyperalgesia. This sensitization phenomenon was not observed in animals previously treated with systemic capsaicin. Likewise, in animals not treated with capsaicin, use of an intravenous antagonist for CGRP [human CGRP-(8-37)], completely reversed the sensitizing effects of acetic acid. Furthermore, intravenous administration of CGRP dose dependently increased the number of abdominal contractions in response to colorectal distension from 3.0 +/- 1.1 (CGRP 250 ng) to 17.0 +/- 1.2 (CGRP 500 ng, P < 0.05), as previously observed in acetic acid-treated animals. Finally, intrathecal administration of hCGRP-(8-37) (mid-lumbar) also resulted in a total dose-dependent reversal of CGRP (500 ng) or acetic acid-induced visceral hypersensitivity. These results demonstrate that CGRP plays a major role in this model of visceral afferent nerve sensitization from gastrointestinal origin.
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