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

Abstract

It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1R) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar9, Met(O2)11-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1 μM) or an equal volume of 1 μM of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21–24 days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5–28 days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund’s adjuvant (CFA) (prolonged hyperalgesia). The proportion of NK-1R-labeled neurons in the RVM was 8.8 ± 1.3% in naïve rats and 8.1 ± 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.

Increased neuronal expression of neurokinin‐1 receptor and stimulus‐evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury

“…The percentage of neurons with NK1R internalization was similar in saline‐treated rats that did or did not experience heat stimulation. Of note, responsiveness to noxious stimuli was not altered by microinjection NK1R receptor antagonists in saline‐treated rats (Hamity et al, ) or ablation of NK1R‐immunoreactive neurons (Khasabov and Simone, ). Taken together, these observations suggest that in the absence of injury Sub P is neither tonically nor phasically released to a significant extent in the RVM.…”

“…These same antagonists are without effect in the absence of injury. Similarly, chemical ablation of RVM neurons that express the NK1R diminishes heat hyperalgesia and mechanical hypersensitivity evoked by intraplantar (ipl) injection of capsaicin, but does not alter responsiveness to heat or mechanical stimuli in the absence of injury (Khasabov and Simone, ). Collectively, these findings strongly support the proposal that Sub P assumes a pronociceptive role in the RVM under conditions of inflammatory injury.…”

The activation of supraspinal GPR40/FFA1 receptor signalling regulates the descending pain control system

“…However, the numbers of the merged cells, especially c-fos and TPH double-positive cells, were fewer than that of c-fos-positive cells. Generally, neurons in the RVM are involved in descending modulation of nociceptive transmission in the spinal cord (Ossipov et al, 2010;Khasabov and Simone, 2013). RVM neurons are two distinct population 'on-cells' and 'off-cells' (Fields et al, 1983).…”

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

“…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). …”

“…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). These data collectively implicate SubP in the RVM in the development and maintenance of a persistent pain state after peripheral inflammatory injury.…”