Changes in Gene Expression and Neuronal Phenotype in Brain Stem Pain Modulatory Circuitry After Inflammation

Abstract

Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. J Neurophysiol 87: 750 -760, 2002; 10.1152/jn.00534.2001. Recent studies indicate that descending pain modulatory pathways undergo time-dependent changes in excitability following inflammation involving both facilitation and inhibition. The cellular and molecular mechanisms of these phenomena are unclear. In the present study, we examined N-methyl-Daspartate (NMDA) receptor gene expression and neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in pain modulatory circuitry, after complete Freund's adjuvant (CFA)-induced hindpaw inflammation. The reverse transcription polymerase chain reaction analysis indicated that there was an upregulation of mRNAs encoding NMDA receptor subunits in the RVM after inflammation. The increase in the NR1, NR2A, and NR2B receptor mRNAs started at 5 h, maintained for 1-7 days (P Ͻ 0.05-0.001) and returned to the control level at 14 days after inflammation. Western blot analysis indicated that the protein translation products of the NR2A subunit were also increased (P Ͻ 0.01). In single-unit extracellular recordings, we correlated RVM neuronal activity with the paw withdrawal response in rats with inflammation. We describe these RVM cells as on-, off-, and neutral-like cells because of their similarity to previous studies in which neuronal responses were correlated with tail-flick nocifensive behavior in the absence of inflammation. In contrast to previous studies in the absence of inflammation, using tail flick as a behavioral correlate, fewer off-like cells in naïve animals exhibited a complete pause before the paw withdrawal to a noxious thermal stimulus. The percentage of cells showing a pause of activity after noxious stimulation was further reduced after inflammation ( 2 P Ͻ 0.0001 vs. naïve rats). Continuous neuronal recordings (3-6.5 h) revealed a phenotypic switch of RVM neurons during the development of inflammation: 11/15 neutral-like cells initially unresponsive to noxious stimuli exhibited and maintained response profiles characteristic of pain modulatory neurons (became off-like: n ϭ 5; became on-like: n ϭ 6). Neutral-like cells recorded in noninflamed animals did not show response profile changes during continuous recordings (5-5.5 h, n ϭ 7). A population study (n ϭ 165) confirmed an increase in on-and off-like cells and a decrease in neutral-like cells at 24 h after inflammation as compared with naïve rats (P Ͻ 0.001). These results suggest that enhanced NMDA receptor activation mediates time-dependent changes in excitability of RVM pain modulatory circuitry. The functional phenotypic switch of RVM neurons provides a novel mechanism underlying activity-dependent plasticity and enhanced net descending inhibition after inflammation.

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

“…Upregulation of mRNAs encoding NMDA receptor subunits, such as NR1, NR2A, and NR2B, has been observed in the RVM after inflammation. 18 Electrophysiological data, however, have been lacking for the functional upregulation of NMDA receptor-mediated responses in these studies. Microinjection of selective NMDA receptor antagonists prevented the inflammation-induced increase in RVM excitability.…”

“…For instance, in PAG and RVM, all receptor subtypes (NR1 and NR2A-D) are expressed. 18 In the human thalamus, the relative abundance of NMDA receptor transcripts was observed as NR2A Ͼ NR2B Ͼ NR2D Ͼ NR2C. 19 In pain-related cortical areas, NR2A and NR2B are predominantly expressed.…”

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

“…91 However, after neuropathic and/or inflammatory pain, the hyperexcitability of nociceptive ascending neurons also causes a sensitization of 'ON'-RVM neurons by overexpression of NMDA/AMPA, Trk-B and NK1 receptors, whereas mu opioid receptor expression decreases. 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).…”

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

“…The RVM, consisting of the nucleus raphe magnus and adjacent nuclei, is a major source of descending pathways to the spinal dorsal horn. In addition to well-known inhibitory influences, descending projections from the RVM facilitate responses of spinal nociceptive neurons (Guan et al 2002;Urban and Gebhart 1999;Urban et al 1996) and contribute to persistent pain and hyperalgesia (Porreca et al 2002;Vanderah et al 2001). Behavioral studies showed that descending facilitation plays a role in inflammatory (Ren and Dubner 1996;Terayama et al 2002), neuropathic (Pertovaara et al 1997;Pertovaara and Wei 2003;Suzuki et al 2004a), and cancer (Dono- van-Rodriguez et al 2006) pain.…”