The Role of The Rostral Ventromedial Medulla in Stress Responses

Abstract

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders.

Keywords: chronic pain; endocannabinoid system; opioid system; pain; pain chronification; stress-induced analgesia; stress-induced hyperalgesia.

Figure 1

Scheme of the major connections projecting, directly or indirectly, to the RVM. This circuitry is critical in modulating the descending and ascending pain pathways. Arrows in red indicate the ascending pain pathway that conveys nociceptive signals from the spinal cord to supra-spinal structures responsible for pain processing—these ascending signals relay in the periaqueductal gray (PAG) and thalamus (THA). The latter sends projections to the primary and secondary somatosensorial cortices (S1 and S2) and anterior cingulate cortex (ACC). Arrows in blue indicate the descending pain pathway, which modulates the ascending information by facilitating or inhibiting its signals. The key structure of the descending pain modulation system is the rostral ventromedial medulla (RVM), which receives major projections from the PAG. The PAG-RVM pathway is one of the best-studied circuits in the descending pain modulation system. Its activation facilitates and inhibits pain. Both structures, the PAG and RVM, receive inputs from the hypothalamus (HYP), a well-known structure implicated in the modulation of stress responses. The PAG also receives inputs from the amygdala (AMY), which is also implicated in stress responses. Finally, the ACC sends projections to the AMY, indirectly influencing the descending pain modulation, and to the RVM, directly influencing the descending pain modulation output. Hence, the RVM maintains, directly or indirectly, neuronal connections with most pain-engaged structures, providing a mechanism in which cortical and subcortical structures influence nociceptive input and pain perception. Therefore, this circuitry is a critical neuroanatomical substrate for stress-induced alterations in nociceptive sensitivity.

Figure 2

RVM mechanisms involved in the generation of acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH). (A) In general, SIA involves the activation of RVM off-cells, which triggers a decrease in the nociceptive response, generating analgesia. Decreases in endocannabinoid-mediated neurotransmission and the antagonism of µ-opioid receptors in the RVM block SIA. On the other hand, the antagonism of serotonergic receptors, the activation of opioid receptors in the BLA, and the potentiation of endocannabinoid-mediated neurotransmission in the RVM facilitate SIA. (B) SIH involves the activation of RVM on-cells, which triggers an increase in the nociceptive response, i.e., hyperalgesia and allodynia. The ablation of µ-opioid receptor-expressing neurons in the RVM blocks SIH, while CCK released from DMH and increased serotonin-mediated neurotransmission in the RVM potentiate SIH. Green arrows indicate activation, and red lines indicate inhibition. BLA: basolateral amygdala; PAG: periaqueductal grey; CCK: cholecystokinin, an anxiogenic and stress-related agent; DMH: dorsomedial nucleus of the hypothalamus.