Rostral ventromedial medulla contributes to stress-induced depression and pain

It is well known that spinal sensory transmission receives descending modulation from the rostral ventromedial medulla (RVM).5,6,14 This modulation is biphasic, and different neurotransmitters and modulators contribute to this biphasic modulation. At synaptic levels, both facilitation and inhibition of spinal synaptic transmission may contain presynaptic regulation of sensory transmitter releases and the regulation of postsynaptic receptors.13,14 Regulation of spinal local inhibitory neurons may also indirectly contribute to biphasic modulation. Neurons in the RVM are likely mixed, divided into on-cells, off-cells, and neutral-cells.7,9 Activation of different groups of neurons may contribute to the facilitation or inhibition of pain. While chronic pain is a major medical problem that is poorly controlled by conventional medicines, chronic emotional stress and its related anxiety and depression are becoming major societal problems. The interaction between pain (including chronic pain) and negative emotions, such as anxiety or depression, has been reported in disease conditions.12,13 There is a great need to investigate the basic mechanisms of network, synaptic, and molecular for these diseases. Among different animal models, chronic social defect stress (CSDS) is a useful model for studying stress-induced behavioral impairments associated with depression in rodents. Different brain circuits have been previously reported to contribute to CSDS. Among them, the RVM is closely linked to brain structures associated with pain and stress, such as the anterior cingulate cortex (ACC), insular cortex, nucleus accumbens (NAc), amygdala, and hypothalamus.7,9,10 Previous studies of RVM are mainly focused how it may contribute to pain or emotional modulation in chronic pain conditions, less is known if it may contribute to depression or pain in case of chronic stress. In a recent issue of PAIN, using chemogenetics to activate or inhibit the RVM during stress, Pagliusi et al. demonstrated that the RVM is an important hub for influencing stress outcomes. Previous studies have shown that chronic or repeated stress facilitates pain, resulting in the phenomenon of stress-induced hyperalgesia (SIH).7 In their study, RVM activation during CSDS by a chemogenetic approach ameliorated the major stress outcomes, including social avoidance, allodynia, hyperalgesia, anhedonia, and depression-like behaviors. The results of Pagliusi et al. are consistent with previous evidence that activating RVM leads to analgesia,4 suggesting that the RVM is involved in the regulation of chronic stress-related pain. Such an analgesic effect (or antinociceptive effect, more precisely) may be mediated by descending inhibitory systems from the RVM to the spinal cord.5,6 Alternatively, RVM may act through its supraspinal projections to cortical and related subcortical areas to produce antinociceptive effects. It has been reported that serotonin (5-HT) produces inhibitory modulation of excitatory synaptic transmission in the ACC.11 The ACC is important for pain perception and top–down descending facilitation.3 It is possible that the serotonergic system plays an important role in the RVM-mediated antinociceptive effects. In addition, this is the first study to demonstrate that the RVM is involved in the regulation of depression-related behavior. The most widely accepted hypothesis for depression is the depletion of monoamines in the brain, especially 5-HT. In fact, traditional antidepressants, such as serotonin reuptake inhibitors, which enhance 5-HT transmission, are currently the primary choice for antidepressant treatment.8 Many corticolimbic structures that express 5-HT receptors are involved in mood regulation and the stress response, including the prefrontal cortex (PFC), amygdala, hippocampus, and NAc.8 However, whether there are 5-HT projections between the RVM and these brain areas or whether these projections mediate stress-induced depression remains to be investigated. As opposed to SIH, exposure to an acute stress triggers a reduction in pain responding, a phenomenon described as stress-induced analgesia (SIA). Stress-induced analgesia is mediated by activation of the descending inhibitory pain pathway.2 Pagliusi et al. found that acute RVM inhibition during subthreshold social defeat stress facilitated all stress outcomes. In contrast to activation of RVM-mediated antinociceptive effects, inhibition of RVM-mediated facilitation may be related to the descending facilitation system from the RVM to the spinal cord.14 Interestingly, Pagliusi et al. found that without stressful stimuli, chronic RVM inhibition triggered facilitation of pain, suggesting that this facilitation of nociception is maybe due to inhibition of tonic descending inhibition.14 This study focused on the role of the RVM on SIH/SIA. However, some projections associated with RVM may also cause these effects. Among them, ACC is an important brain region involved in chronic pain and stress outcomes. It is reported that the projection from the basolateral amygdala (BLA) to the ACC contributes to depression-like behaviors and comorbidity with chronic pain behaviors.1 The projections from the ACC to the RVM are involved in the descending facilitation of pain.13 Thus, the RVM could serve as the final hub in this circuitry, making it participated in both chronic pain and depression-like behaviors. Current studies tend to focus on the role of a specific brain region or a specific neurotransmitter in stress-induced chronic pain and depression-like behaviors. Future studies should focus on projective connections between different brain regions, as well as cross talk between different neurotransmitter and receptor systems to better understand stress-induced comorbidities. In summary, the work by Pagliusi et al. provides useful models for understanding stress-induced comorbidity between chronic pain and depression. This study suggests the RVM involved in mediating chronic pain and depression-like behaviors induced by social stress, providing new insights into understanding the comorbidity between pain and depression. However, in this paper, only behavioral functional tests were performed, and there are multiple future research directions, which include synaptic and molecular mechanisms of the RVM, as well as different projection pathways and cell types, can be studied for stress-induced chronic pain and depression-like behaviors. Rostral ventromedial medulla, which includes the nucleus raphe magna and its surrounding ventral reticular structure,5 is nonhomogenous, and their study did not specifically distinguish activated subnuclei and specific cell types, and more experiments are needed in the future. In addition, the social defeat stress model in this study was only applicable to male rodents and did not consider the effects of sex and sex hormones on SIH/SIA. If it is necessary to study the effects of the RVM on SIH/SIA in different genders, another stress model applicable to female rodents should be explored. Conflict of interest statement The authors have no conflict of interest to declare.

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