Cellular basis for the effects of substance P in the periaqueductal gray and dorsal raphe nucleus

Abstract

Substance P (SP) is known to act at supraspinal sites to influence pain sensitivity as well as to promote anxiety. The effects of SP could be mediated in part by actions in the periaqueductal gray (PAG) and the dorsal raphe nucleus (DRN), adjoining mesencephalic cell groups that are strategically positioned to influence both nociception and mood. Previous studies have indicated that SP regulates both enkephalin and serotonin neurotransmission in these brain regions. To determine the mechanism underlying the effects of SP in the PAG and DRN, the distribution of the principal receptor for SP, the neurokinin 1 (NK1) receptor, was examined with respect to other neurotransmitter markers. PAG neurons that had NK1 receptor immunolabeling were interdigitated with and received contacts from enkephalin-containing neurons. However, only a few (16/144; 11%) neurons with NK1 receptor also contained enkephalin immunoreactivity after colchicine treatment. In the DRN, dendrites containing NK1 receptor were selectively distributed in the dorsomedial subdivision. The majority (132/137; 96%) of these dendrites did not contain immunoreactivity for the serotonin-synthesizing enzyme tryptophan hydroxylase. In contrast, neuronal profiles with NK1 receptor in both the PAG and the DRN often contained immunolabeling for glutamate. Light and electron microscopic examination revealed that 48-65% of cell bodies and dendrites with NK1 receptor were dually immunolabeled for glutamate. These data suggest that SP directly acts primarily on glutamatergic neurons in the PAG and DRN. To a lesser extent, enkephalin-containing neurons may be targeted. Through these actions, it may subsequently influence activity of larger populations of neurons containing enkephalin as well as serotonin. This circuitry could contribute to, as well as coordinate, effects of SP on pain perception and mood.

A Neurochemically Distinct Dorsal Raphe-Limbic Circuit with a Potential Role in Affective Disorders

“…Therefore, in this study the distribution of NK1 receptor with respect to CRF-containing cells in the DR was examined. Consistent with previous findings that NK1 receptor is present in nonserotonin-containing cells and dendrites in the DR (Commons and Valentino, 2002;Santarelli et al, 2001), NK1 receptor immunoreactivity was not colocalized with CRF or TPH immunoreactivity (Figure 3). Rather, dendrites labeled with NK1 receptor radiated in a striking pattern around CRF/serotonin cells in the dorsomedial part of the DR (Figure 3).…”

“…Previously, we and others reported the distribution of NK1 receptor in the DR of the rat (Commons and Valentino, 2002) and mouse (Santarelli et al, 2001). In both species, dendrites with NK1 receptor immunoreactivity were found to selectively surround the dorsomedial DR.…”

Effects of Substance P in the Amygdala, Ventromedial Hypothalamus, and Periaqueductal Gray on Fear-Potentiated Startle

“…The VMH also projects to the vlPAG, particularly, to its more caudal elements (Canteras et al, 1994), but it is unknown whether these projections also contain SP. Although SP receptors are distributed throughout the PAG (Barbaresi, 1998;Commons and Valentino, 2002), our data indicate that those in the caudal vlPAG play a less significant role in fear-potentiated startle.…”

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

“…VGLUT3-positive terminals within the raphe arise either from 5HT neurons or from local VGLUT3-only glutamatergic neurons. Glutamatergic raphe neurons were recently shown to send projections (1) to the hippocampus and the septum (Jackson et al, 2009) and (2) locally to the dorsolateral subdivision of the DRN (Commons and Valentino, 2002;Valentino et al, 2003). In Vglut3 Ϫ/Ϫ mice, the lack of VGLUT3 in these glutamatergic fibers somehow triggers the desensitization of 5-HT 1A receptors.…”