Species differences in tachykinin receptor distribution: Further evidence that the substance P (NK₁) receptor predominates in human brain

Abstract

Marked species differences in the distribution of central tachykinin receptors are reported but uncertainty remains about the ability of available ligands to detect NK2 and NK3 receptors in human brain. We compared the distribution of NK1, NK2, and NK3 receptors in sections from rodent, primate, and human brain using the 125I-labeled ligands substance P (SP) for the NK1 receptor, neurokinin A (NKA) for the NK2 receptor, and neurokinin B (NKB) and eledoisin for NK3 receptors. Duration of exposure to autoradiographic film was from 7 days for [125I]SP up to 90 days for the other ligands. High levels of specific [125I]SP binding were seen throughout the brains of all species studied. Specific [125I]NKA binding was detected in brains from neonatal rat, and to a lesser level in adult rat, gerbil, and guinea pig; it was not detected in monkey or human brain, but was present in circular muscle of human duodenum, confirming that this ligand binds to human NK2 receptors under our experimental conditions. Specific [125I]NKB and [125I]eledoisin binding was widespread in brain sections from rats, gerbils, and guinea pigs, and very low levels were also detected in marmoset, squirrel monkey, and rhesus monkey brain after prolonged (up to 90 days) exposure. We failed to identify specific eledoisin binding in human brain, even after prolonged exposures. These findings demonstrate that the NK1 receptor is the predominant tachykinin receptor expressed in primate and human brain, but that low levels of NK3 receptor are present in nonhuman, primate brain.

In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia

“…However, no NK 3 receptors have been detected, to date, within the mesencephalic dopaminergic neurons (Dietl and Palacios, 1991;Whitty et al, 1994Whitty et al, , 1997. Thus, in addition to the complications of using preclinical species to evaluate the functional role of the NK 3 receptors, there is also some controversy with regard to the specific localization and density of NK 3 receptors within the human brain (Rigby et al, 2005). Although, in this regard our in house studies, using autoradiographic and immunohistochemical techniques, have detected widespread but low-level expression of the NK 3 receptors within human brain (unpublished data).…”

“…In the mammalian brain, NK 3 receptors are expressed within medial prefrontal cortex (mPFC), thalamus, and amygdala, while their presence in midbrain dopaminergic nuclei (the ventral tegmental area (VTA) and substantia nigra (SN)), locus coeruleus, and septal and basal nuclei suggest a role in modulating central monoaminergic systems (Langlois et al, 2001). However, there are considerable species differences in NK 3 receptor expression within the brain (Langlois et al, 2001;Rigby et al, 2005) which can complicate preclinical investigations of this receptor.…”

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…The NK3 receptor in the brain typically is found in cortical regions, nuclei of amygdala, hippocampus as well as midbrain structures e.g. substantia nigra, ventral tegmental area and raphe nuclei [208]- [210]. However, it is present in the cerebral regions in low density in comparison with NK1 and NK2 receptors [211].…”

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

“…Three types of G-protein-coupled receptors, denoted NK 1 , NK 2 , and NK 3 , mediate a wide range of biological activities of tachykinins. Neuroanatomical studies have demonstrated that the NK 1 receptor is predominant in the human brain, whereas the expression of NK 2 or NK 3 receptors is either weak or absent (3). NK 1 receptors are widely expressed throughout the central nervous system (3) and are involved in the regulation of various behavioral, endocrine, and autonomic functions.…”

“…Neuroanatomical studies have demonstrated that the NK 1 receptor is predominant in the human brain, whereas the expression of NK 2 or NK 3 receptors is either weak or absent (3). NK 1 receptors are widely expressed throughout the central nervous system (3) and are involved in the regulation of various behavioral, endocrine, and autonomic functions. Based on the pharmacological data and recent clinical trials, it has emerged that blockade of brain tachykinin NK 1 receptors may provide a novel treatment of emesis (4,5), major depression (6), and anxiety problems (7).…”