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.

Keywords: RVM; analgesia; brainstem; descending control; hyperalgesia; pain-modulation; rostral ventromedial medulla.

Figure 1

Top-down and bottom-up inputs through which cognitive and emotional factors could influence nociceptive transmission by modulating the firing of RVM pain-modulating neurons. Cognitive and emotional processes mediated by higher structures have the potential to influence the RVM through the PAG, and in some cases, directly. Bottom-up, nociceptive, inputs are relayed from the spinal cord to the RVM via the parabrachial complex. ACC: anterior cingulate cortex; Amg: amygdala; Hyp: hypothalamus; m-PFC: medial prefrontal cortex; PAG: periaqueductal gray; PB: parabrachial complex; RVM: rostral ventromedial medulla. Adapted from Cleary, D. and Heinricher, M.M. Neuroanatomy and neurophysiology of pain. In Winn, H.R. (Ed)., Youmans and Winn Neurological Surgery, 8th Ed., Elsevier Saunders, Philadelphia, 2022.

Figure 2

Reciprocal firing patterns of pain-modulating RVM ON- and OFF-cells. Examples of ON- and OFF-cell firing changes associated with nocifensive withdrawal evoked by a noxious heat stimulus. The OFF-cell pauses and ON-cell bursts immediately prior to the behavior. The threshold at which the OFF-cells pause correlates with the threshold for nocifensor withdrawals and periods of OFF-cell inactivity are associated with a lower threshold (16). In contrast, the magnitude of the ON-cell burst is positively correlated with the magnitude of behavioral responses (17). Heat (bottom trace) was applied to the plantar surface of the hind paw using a Peltier device. Withdrawal reflex was monitored using an electromyogram (EMG). The OFF-cell “pauses” and ON-cell “bursts” immediately prior to the withdrawal. The duration of the pause and burst can range from a few seconds, as here, to many minutes.