NK-1 Receptors Modulate the Excitability of on Cells in the Rostral Ventromedial Medulla

Abstract

. The role of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM) was studied using extracellular single-unit recording combined with microiontophoresis. In rats, ON-and OFF-type neurons were identified using noxious heat or mechanical stimuli applied to the tail. Responses evoked by iontophoretic application of N-methyl-D-aspartate (NMDA) were determined before and after intraplantar injection of capsaicin or iontophoretic application of substance P. In OFF cells, capsaicin produced an extended pause in ongoing activity but did not alter the subsequent spontaneous discharge rate or NMDA-evoked responses. In contrast, spontaneous discharge rates of ON cells increased after capsaicin, and their responses to NMDA increased Ͼ100% above control values. The increased responses to NMDA after capsaicin were attenuated by iontophoretic application of the selective NK-1 receptor antagonist L-733,060. Similarly to capsaicin, iontophoretic application of the selective NK-1 receptor agonist, [Sar 9 ,Met(O 2 ) 11 ]-substance P (SM-SP), increased the spontaneous discharge rate and NMDA-evoked responses of ON cells by Ͼ100% of control values. These effects were antagonized by L-733,060. Immunohistochemical studies showed that a subset of neurons in the RVM labeled NK-1 receptors and that nearly all of these neurons were immunoreactive for the NMDAR1 subunit of the NMDA receptor. These results demonstrate that activation of NK-1 receptors in the RVM enhances responses of ON cells evoked by NMDA. It is suggested that activation of NK-1 receptors in the RVM and the ensuing sensitization of ON cells may contribute to the development of central sensitization and hyperalgesia after tissue injury and inflammation.

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

“…Neural plasticity throughout the pain axis (Abbadie et al, 1996;Malcangio et al, 2000;Vanderah et al, 2001;Szücs et al, 2004;King et al, 2005;Wan et al, 2006;Budai et al, 2007;Christie, 2008;Richebe et al, 2012), gastrointestinal (GI)/ emesis axis (Bountra et al, 1993;Hargreaves et al, 2011), and reward pathways (Maldonado et al, 1993;Powell et al, 2003) includes enhanced signaling of substance P through NK 1 receptors, resulting from chronic pain and opioids. These data Using an Opioid Agonist/NK1 Antagonist for Chronic Pain suggest that targeting multiple molecular components may translate into safer and more efficacious pain therapeutics (Woodcock et al, 2007).…”

“…Anatomic (Aicher et al, 2000;Wan et al, 2006) and system-based interactions between opioids and SP-NK 1 Cahill and Coderre, 2002;King et al, 2005) have been reported. SP content/release is altered in injury (Abbadie et al, 1996;Malcangio et al, 2000) and after sustained opioids (King et al, 2005;Lu et al, 2011) with enhanced activation of NK 1 receptors throughout the nociceptive axis (Budai et al, 2007). The SP-NK 1 system is implicated in the mechanisms underlying opioid antinociceptive tolerance, withdrawal, and reward (Commons, 2010).…”

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

“…Under these circumstances, 'ON'-RVM neurons do not respond to inhibitory signals from PAG, whereas they are highly stimulated by ascending inputs (Figure 4) 86,92,93 that release glutamate, SP and dynorphin over thalamic and brainstem neurons including 'ON'-RVM cells. [84][85][86][87][88][89][90][91][92][93][94][95][96] In summary, all these neurotransmitters released by nociceptive ascending neurons over 'ON'-RVM neurons cause their hyperexcitability (Figure 4). 97 Neuropathic and inflammatory pain also causes changes in PAG neurons.…”

“…[86][87][88][89][90] PAG neurons release β-endorphin over 'ON'-RVM neurons causing hyperpolarization via mu opioid receptor, and the descending facilitation from 'ON' neurons is inhibited. 83 In addition, the stimulation of TRPV1 receptor also inhibits 'ON'-RVM neurons (Figure 4).…”

Imaging Drugs with and without Clinical Analgesic Efficacy

“…Preclinical studies have demonstrated that antagonist action on NK 1 receptors attenuated the behavioral response to noxious stimulation (Xu et al, 1992). Suzuki et al (2003) showed an attenuation of electrophysiological responses to noxious heat in the dorsal horn neurons in NK 1 receptor-knockout mice, whereas Budai et al (2007) reported diminished activity of on-cells in rostral ventral medulla following application of an NK 1 receptor antagonist (L-733,060). The source of potentation in the supraspinal limbic circuitry observed here could arise from the coupling between antagonist action on NK 1 receptors and the 5-HT system (Gobert et al, 2009;Valentino et al, 2003).…”