Differential modulation of neurons in the rostral ventromedial medulla by neurokinin-1 receptors

Abstract

The rostral ventromedial medulla (RVM) is part of descending circuitry that modulates nociceptive processing at the level of the spinal cord. RVM output can facilitate pain transmission under certain conditions such as inflammation, and thereby contribute to hyperalgesia. Evidence suggests that substance P and activation of neurokinin-1 (NK-1) receptors in the RVM are involved in descending facilitation of nociception. We showed previously that injection of NK-1 receptor antagonists into the RVM attenuated mechanical and heat hyperalgesia produced by intraplantar injection of capsaicin. Furthermore, intraplantar injection of capsaicin excited ON cells in the RVM and inhibited ongoing activity of OFF cells. In the present studies, we therefore examined changes in responses of RVM neurons to mechanical and heat stimuli after intraplantar injection of capsaicin and determined the role of NK-1 receptors by injecting a NK-1 receptor antagonist into the RVM prior to capsaicin. After capsaicin injection, excitatory responses of ON cells and inhibitory responses of OFF cells evoked by mechanical and heat stimuli applied to the injected, but not contralateral, paw were increased. Injection of the NK-1 antagonist L-733,060 did not alter evoked responses of ON or OFF cells but attenuated the capsaicinevoked enhanced responses of ON cells to mechanical and heat stimuli with less of an effect on the enhanced inhibitory responses of OFF cells. These data support the notion that descending facilitation from RVM contributes to hyperalgesia and that NK-1 receptors, presumably located on ON cells, play an important role in initiating descending facilitation of nociceptive transmission.

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

“…Our behavioral studies showed that loss of these neurons in the RVM did not alter withdrawal responses to acute mechanical or thermal stimuli but decreased hyperalgesia produced by intraplantar injection of capsaicin or prolonged hind paw inflammation. These findings are consistent with earlier studies and provide additional evidence that neurons in the RVM that express NK-1Rs are part of descending circuitry that facilitates nociception (Pacharinsak et al, 2008; Hamity et al, 2010; Lagraize et al, 2010; Brink et al, 2012; Khasabov et al, 2012). …”

“…We also showed that sensitization of ON cells to cutaneous stimulation following capsaicin (Brink et al, 2012) or prolonged inflammation (Khasabov et al, 2012) was reduced by an NK-1R antagonist. Although these studies showed that activation of NK-1Rs can enhance activity of ON cells and thereby contribute to facilitation of nociceptive transmission, this approach has limitations to understanding the role of NK-1R expressing RVM neurons because NK-1Rs are only a part of neurochemical mechanisms that regulate activity of these neurons.…”

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

“…Using this approach, no increase in SubP content was observed on either side of the RVM four hours, four days, or two weeks after CFA treatment. This negative finding was not congruent with the results of earlier pharmacological (Pacharinsak et al, 2008; Hamity et al, 2010; Lagraize et al, 2010), electrophysiological (Budai et al, 2007; Zhang and Hammond, 2009; Brink et al, 2012) and neuroanatomical (Hamity et al, 2014) investigations whose results suggested that CFA treatment may increase SubP release. Measurements in tissue homogenates may not be able to detect small changes in content, changes that are confined to subsets of neurons or changes that occur in specific compartments such as axon terminals.…”

“…The mechanisms by which it acts in the periphery and spinal cord to induce and maintain heat hyperalgesia and mechanical hypersensitivity after peripheral inflammatory injury are well characterized (see reviews by (Baranauskas and Nistri, 1998; Sandkuhler et al, 2000; Snijdelaar et al, 2000; Mantyh, 2002; Keeble and Brain, 2004; Seybold, 2009; Todd, 2010; Steinhoff et al, 2014). Our understanding of its actions within supraspinal nuclei that modulate the transmission of nociceptive information in the spinal cord continues to evolve, particularly with respect to its actions in the rostral ventromedial medulla (RVM) (Lagraize et al, 2010; Hahm et al, 2011; Brink et al, 2012; Khasabov and Simone, 2013; Hamity et al, 2014). …”

“…In uninjured animals, a single injection or continuous infusion of SubP into the RVM causes hypersensitivity of the hindpaw to noxious heat stimuli that can last 24 hours (Hamity et al, 2010; Lagraize et al, 2010). Microinjection of NK1R antagonists into the RVM of animals with inflammatory injury induced by capsaicin or complete Freund's adjuvant (CFA) prevents and reverses thermal hypersensitivity, while in uninjured animals, delivery of these same NK1R antagonists into the RVM does not interfere with their normal behavioral responsiveness to thermal or mechanical stimuli (Pacharinsak et al, 2008; Hamity et al, 2010; Lagraize et al, 2010; Brink et al, 2012). Chemical ablation of NK1R in the RVM also blocks thermal and mechanical sensitivity following capsaicin and CFA-induced inflammation (Khasabov and Simone, 2013).…”