Gender and age affect NK1 receptors in the human brain – a positron emission tomography study with [18F]SPA-RQ

Abstract

Substance P (SP) is a neurotransmitter and neuromodulator that mediates its effects in the brain predominantly via the neurokinin-1 receptors (NK1Rs). NK1Rs and SP have been shown clinically to be involved in nausea and emesis after chemotherapy (CINV) and have been implicated preclinically in a range of neuropsychiatric disorders but unlike CINV their blockade in these conditions does not have proven clinical value. We investigated whether age and gender affects NK1R binding potential (NK1R-BP; an index of receptor availability) in the living human brain using PET and [18F]SPA-RQ, a highly specific NK1R antagonist. Forty-five healthy volunteers (35 male and 10 female), aged between 19 and 55 years were studied. NK1R-BP was estimated using the simplified reference tissue model with cerebellum as a reference region. A regression analysis indicated that that a loss of NK1R is associated with normal ageing as shown by decreased NK1R-BP (average rate 7% per decade). Statistically significant negative associations between age and NK1R-BP were observed in temporal, parietal and frontal cortex, hippocampus and parahippocampal formation. In addition preliminary data were obtained suggesting possible gender differences in NK1R-BP in the cortex and putamen with females having a lower NK1R-BP. The exact physiological significance of these results remains to be elucidated but conceptually they could be involved in age-related CNS disorders or those with gender differences in prevalence.

Detection of full-length and truncated neurokinin-1 receptor mRNA expression in human brain regions

“…In addition, the full-length NK1R mRNA expression levels in the putamen was significantly higher than that in the cerebellum (P= 0.025). Considering that the binding affinity of the full-length NK1R to SP, its preferred agonist, is much higher (at least 10 fold) than that of the truncated NK1R (Fong et al, 1992), our data is in agreement with a recent report (Nyman et al, 2007) which demonstrated that putamen had the highest binding potential in the living human brain using PET and [ 18 F]SPA-RQ, a highly specific NK1R antagonist. Although the existence and expression of both the full-length and truncated NK1R have been documented, the differences in their expression in human brain tissue have been investigated only to a limited extent.…”

Sex and the migraine brain

“…Positron emission tomography (PET) studies indicate that sex influences brain expression of dopamine (129, 130), serotonin (131), neurokinin 1 (132, 133), and opioids (134). Autoradiography studies in rodents further indicate sex differences in AMPA, kainate, and NMDA (135) as well as noradrenergic transmission (136).…”

Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain

“…NK-1R availability was quantified with the radioligand [ 18 F]SPA-RQ, a high-affinity NK-1R antagonist [29,58,73]. Images were acquired using a Siemens ECAT EXACT HR+ scanner (Siemens Healthcare Solutions, Deerfield, IL, USA: in-plane resolution full-width at half-maximum [FWHM] = 4.6 mm, axial FWHM = 3.5 mm, axial field of view = 15.52 cm) in 3-dimensional (3D) mode.…”