Shifting the Balance: How Top-Down and Bottom-Up Input Modulate Pain via the Rostral Ventromedial Medulla

Abstract

The sensory experience of pain depends not only on the transmission of noxious information (nociception), but on the state of the body in a biological, psychological, and social milieu. A brainstem pain-modulating system with its output node in the rostral ventromedial medulla (RVM) can regulate the threshold and gain for nociceptive transmission. This review considers the current understanding of how RVM pain-modulating neurons, namely ON-cells and OFF-cells, are engaged by “top-down” cognitive and emotional factors, as well as by “bottom-up” sensory inputs, to enhance or suppress pain.

Brainstem pain-modulating neurons are sensitized to visual light in persistent inflammation

“…The graded response to light, and the response to dim levels of light, are in contrast with the response to somatic stimulation, in which RVM cells respond in an all-or-nothing manner and only to stimuli that evoke a nocifensive withdrawal ( Fields et al, 1983 , Cleary and Heinricher, 2013 ). Noxious somatic input forms a recurrent loop with RVM in which noxious somatic stimuli act as a bottom-up input to RVM, causing a change in RVM cell activity that in turn modulates nociceptive transmission, and ultimately influences the behavioral response threshold ( Hernandez et al, 1994 , Chen and Heinricher, 2022 ). The present data suggest that light instead acts as a top-down input that can influence the excitability of the pain-modulation system through graded changes in RVM cell activity.…”

Mild Traumatic Brain Injury–Induced Augmented Postsurgical Pain Is Driven by Central Serotonergic Pain-Facilitatory Signaling

“…The endogenous opioid system is important in modulating the descending pain-facilitating pathway and contributes to latent sensitization. 20 To test for the state of latent sensitization in post-mTBI mice, naloxone, a mu-opioid receptor (MOR) antagonist, was administered as outlined by Marvizon et al 21 The withdrawal thresholds in each treatment group were allowed to recover to the level of the sham-mTBI/sham-incised group. Then, on the day of the naloxone experiment, the animal’s abdominal skin was cleaned with an alcohol pad, and 1 mg/kg naloxone (Sigma Life Science, 50 μg/100 μL, diluted in saline) was administered intraperitoneally (i.p.).…”

Leveraging Endogenous Pain Modulation for Analgesia

“…For instance, factors, such as stress, hunger, and attention, have been shown to influence pain sensitivity. 5 A significant body of "This article is an important part of recent advancements in our understanding of how higher brain areas exert 'topdown' controls of our pain sensitivity." Q. Chen and J. D. Clark Editorial work in the past 40 yr has been devoted to characterizing the output of a major pain modulation system composed of the periaqueductal grey and rostral ventromedial medulla in the brainstem.…”

“…This brainstem circuit projects to the spinal dorsal horn, where its output has the dual ability to suppress and promote nociceptive processing and signal transmission to the brain. 5 Increasingly, questions on how the input from higher brain centers, such as the anterior cingulate cortex and amygdala, mediates the brainstem pain-modulating circuit to fine-tune pain sensitivity are becoming important areas in pain neuroscience research.…”

“…For instance, factors, such as stress, hunger, and attention, have been shown to influence pain sensitivity. 5 A significant body of work in the past 40 yr has been devoted to characterizing the output of a major pain modulation system composed of the periaqueductal grey and rostral ventromedial medulla in the brainstem. This brainstem circuit projects to the spinal dorsal horn, where its output has the dual ability to suppress and promote nociceptive processing and signal transmission to the brain.…”