The Brainstem and Nociceptive Modulation

Spinal nociceptive processing is under the control of specific brainstem modulatory circuits. The best studied and probably functionally most significant such modulatory circuit has links in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). This system exerts bidirectional control over nociceptive processing, suppressing, or facilitating nociception under different physiological and pathological conditions. The PAG-RVM system receives substantial inputs from hypothalamus and forebrain, integrating information related to motivation and emotion with visceral and somatic afferent input. This allows top-down control as well as feedback modulation of nociception. Functional characterization of neurons in the RVM reveals two populations of nociceptive modulatory neurons, on- and off-cells. There is now strong evidence that on-cells facilitate nociception and that off-cells inhibit nociception. A similar circuit-level analysis of the PAG, which is implicated in a host of functions from autonomic control to reproductive behavior and vocalization, would greatly advance our understanding of the neural circuitry of pain modulation in this region. The current challenge is to define the mechanisms through which the PAG-RVM modulatory system is brought into play to enhance or inhibit pain.