Different subtypes of tachykinin NK1 receptor binding sites are present in the rat brain

(2-[I-125] iodohistidyl(1))Neurokin in A ([I-125] NKA), which labels septide-sensitive'' but not classic NK1 binding sites in peripheral tissues, was used to determine whether septide-sensitive binding sites are also present in the rat brain. Binding studies were performed in the presence of SR 48968 (NK2 antagonist) and senktide (NK3 agonist) because [I-125]NKA also labels peripheral NK2 binding sites and, as shown in this study, central NK3 binding sites. [I-125]NKA was found to label not only septide-sensitive binding sites but also a new subtype of NK1 binding site distinct from classic NK1 binding sites. Both subtypes of I-125]NKA binding sites were sensitive to tachykinin NK1 antagonists and agonists but also to the endogenous tachykinins NKA, neuropeptide K (NPK), and neuropeptide gamma (NP gamma). However, compounds of the septide family such as substance P(6-11) [SP(6-11)] and propionyl[Met(O-2)(11)]SP(S-11) and some NK1 antagonists, GR 82334, RP 67580, and CP 96345, had a much lower affinity for the new NK1-sensitive sites than for the septide-sensitive sites. The hypothalamus and colliculi possess only this new subtype of NK1 site, whereas both types of [I-125]NKA binding sites were found in the amygdala and some other brain structures. These results not only explain the central effects of septide or SP(6-11), but also those of NKA, NPK, and NP gamma, which can be selectively blocked by NK1 receptor antagonists.