NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

Abstract

The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePhe8, Sar9)SP(5-11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met (O(2))11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met (O(2))11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM.

Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla

“…3). 4) NK1 receptors that bind SP are found in the RVM (Makeham et al, 2005), but whether these receptors co-localize with serotonin containing neurons is inconclusive. 5) Glutamate neurons that inhibit nociceptive responses exist in the RVM (Winkler et al, 2006), as do SP-ir neurons (Menetrey and Basbaum, 1987).…”

“…al‥, 1978), but the connection has not been shown directly. Lastly, NK1 receptors that bind SP are found in the RVM (Makeham et al, 2005).…”

Differential regulation of the central neural cardiorespiratory system by metabotropic neurotransmitters

“…(e) Other peptides As noted earlier, many other peptides play an important role in the tonic and reflex regulation of the cardiorespiratory systems, including substance P (Gilbey et al 1983;Makeham et al 2001Makeham et al , 2005, pituitary adenylate cyclase-activating polypeptide (PACAP; Farnham et al 2008), somatostatin (Burke et al 2008), galanin (Stornetta et al 2009;figure 2b), which is present in many chemosensitive neurons in the retrotrapezoid nucleus, and thyrotropin-releasing hormone (Murphy et al 1995;Sun et al 1995Sun et al , 1996. The effects of these neuromodulators are site specific and in most cases their physiology is still very poorly understood.…”

Neurokinin-1 Receptors Modulate the Excitability of Expiratory Neurons in the Ventral Respiratory Group

“…Although NK1-R are localized throughout the VRG (Gray et al 1999;Guyenet et al 2002;Nakaya et al 1994;Wang et al 2001) with expression confirmed on preinspiratory neurons , the effect of direct activation of NK1-R expressing expiratory neurons on respiratory rhythm has not been thoroughly explored. Although substance P can decrease respiratory frequency by prolonging expiratory duration (Chen et al 1990b;Fong and Potts 2006;Makeham et al 2005), the functional expression of NK1-R on individual expiratory neurons has not been demonstrated. We now provide evidence that exogenous SP modulates the excitability of a subpopulation of E neurons suggesting a possible functional role for NK1-Rs in an expiratory region of the VRG.…”