Descending facilitation

Abstract

It is documented that sensory transmission, including pain, is subject to endogenous inhibitory and facilitatory modulation at the dorsal horn of the spinal cord. Descending facilitation has received a lot of attention, due to its potentially important roles in chronic pain. Recent investigation using neurobiological approaches has further revealed the link between cortical potentiation and descending facilitation. Cortical-spinal top-down facilitation, including those relayed through brainstem neurons, provides powerful control for pain transmission at the level of the spinal cord. It also provides the neuronal basis to link emotional disorders such as anxiety, depression, and loss of hope to somatosensory pain and sufferings. In this review, I will review a brief history of the discovery of brainstem-spinal descending facilitation and explore new information and hypothesis for descending facilitation in chronic pain.

Keywords: Descending facilitation; anterior cingulate cortex; chronic pain; mice; pain; rostroventral medial medulla; serotonin.

Figure 1.

Example of facilitation of responses to non-noxious brush stimulation of the skin produced by stimulation in RMM. (a) Peristimulus time histograms (1-s bin width) and corresponding oscillographic records illustrating a control response to brush of the skin of the hind foot and the effect on responses of the same unit during stimulation in the RMM (intensities given). The brush stimulus is indicated by the horizontal arrows, and the period of RMM stimulation (25 s) is indicated by upward and downward arrows. (b) Graphic representation of the data in (a); the point above 0 represents the response (total number of impulses) in the absence of RMM stimulation. (c) Stimulation site, illustrated on a representative coronal brain section, and receptive field with orientation of brush stimulus indicated. Modified from Zhuo and Gebhart (2002).

Figure 2.

Summary of activation of RVM neurons on visceromotor responses. (a) Mean peristimulus time histograms (PSTHs; 1-s bin width) representing the mean visceromotor response before glutamate administration (unfilled PSTHs) and at 1 min after glutamate administration (filled PSTHs). The period of distention (20 s) is indicated below by the horizontal bar. (b) Graphic representation of the data in (a) and time course of effect. The data are presented as a percentage of the control response (total counts in 20 s). (c) Brainstem sites for glutamate microinjection at a low dose (5 nmol; •) and a greater dose (50 nmol; ○). At three sites (indicated by 䑔), both doses of glutamate (5 and 50 nmol) were tested. Modified from Zhuo and Gebhart (2002).

Figure 3.

Biphasic modulation of spinal synaptic transmission by 5-HT. (a) and (b) Examples of 5-HT experiments at two doses. Upward arrows indicate the time of stimulation. (c) The effect of 5-HT on amplitudes of EPSCs in experiments shown in a (squares) and b (triangles). (d) Summary data of 5-HT at four different doses (n = 8 for each dose). (e) Different effects of 5-HT1A- and 5-HT2 receptor agonists (8-OH-DPAT and DOI, respectively). The effects were blocked by their receptor antagonists NAN-190 (5-HT1A) and methysergide (5-HT), respectively. *P < 0.05. Modified from Li and Zhuo (1998).

Figure 4.

Forskolin and 5-HT synergistically facilitate sensory synaptic transmission. (a) Examples of EPSPs showing synaptic responses before, during, and after co-application of 5 μM 5-HT and 10 μM forskolin. Note that stimulation of primary afferent fibers at the same intensity induced action potentials from the same neuron during the washout. (b) Forskolin (10 μM) alone did not produce any facilitation in a separate experiment. (c) Summarized results for different treatments with forskolin and/or 5-HT. Data are shown as percentages in EPSP slopes during the drug application. While forskolin (10 μM) alone did not induce significant changes in synaptic responses, co-application of 5-HT (5 μM) and forskolin (10 μM) induced long-lasting enhancement of synaptic responses. However, co-application of 5-HT at a high dose (100 μM) with forskolin (10 μM) produced inhibition of synaptic responses during the drug application. Synaptic responses recovered after 10 min washout with normal solution. *P < 0.05 indicates significant difference from control. Modified from Wang et al. (2002).

Figure 5.

Top-down descending projection from the ACC to the spinal cord. (a) Schematic figures and digitized photomicrograph showing Fluoro-Gold (FG) injection site in the spinal cord and retrograde transportation of FG label neurons in the ACC. (b) Distribution of FG-labeled neurons in both sides of ACC after FG injection into the spinal cord. (c) and (d) Augmented figures showing FG (green) and Fos (red) double-labeling results in rectangle area 1 (c) and 2 (d) in b. Arrowheads on the merged figures indicate FG/Fos double-labeled neurons. Modified from Chen et al. (2014).

Figure 6.

Descending facilitation of behavioral withdrawal by optogenetic activation of ACC pyramidal cells. (a) Schematic diagram of viral injection site (left) and optic cannula placement (right) in the ACC. (b) One example of the effects of blue light in a CaMKII-ChR2 expressing mouse (red) and an EYFP expressing mouse (black) in the von Frey test. (c) Pooled data for ChR2 and EYFP mice. On average, there was a reduction in the mechanical threshold in the ChR2 group. The graph on the right plots the combined data for the two ON and three OFF episodes. There was a significant effect of laser light in the ChR2 group but not in the EYFP group. (d) Not all animals showed a decrease of the mechanical threshold during light activation. Out of 18 animals, 10 showed a decrease while 8 did not. (e) The overlapped pattern of ChR2 expression in each group. Modified from Kang et al. (2016).

Figure 7.

Enhanced excitatory transmission in the ACC by chronic visceral pain. (a) Representative mEPSCs recorded in pyramidal neurons at a holding potential of 70mV from control and zymosan-injected mice. (b) Cumulative inter-event interval (left) and amplitude (right) histograms of mEPSCs recorded in slices of control and zymosan-injected mice. (c) Summary plots of mEPSC data. The frequency (left) and amplitude (right) of mEPSCs were significantly enhanced in the ACC slices of mice injected with zymosan. *P < 0.05 versuss control. Modified from Liu et al. (2015).

Figure 8.

Descending facilitation from the ACC. ACC pyramidal cells send projection fibers to the brainstem RVM and activate RVM neurons that send descending projection to the spinal cord dorsal horn. 5-HT is a likely key neurotransmitter for such facilitatory effect on spinal sensory synaptic transmission. Enhanced postsynaptic AMPA receptor-mediated synaptic responses contribute to facilitated effects produced by 5-HT in the dorsal horn. ACC neurons also send its projection directly to the dorsal horn and potentiate spinal sensory synaptic transmission. Glutamate is likely one of these facilitatory transmitters. It may cause the potentiation by presynaptic and/or postsynaptic mechanisms. For the cortical inputs, ACC neurons receive at least sensory input through ascending projection from the spinal cord through the thalamus.