ArticleNeuroscience2013
The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.
Article in Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 42 citations in OpenAlex.
- Subjective risk factors of severe pain at discharge from the emergency department.Internal and emergency medicine · 2025Trial
- The role and interaction of hypothalamic-related neurotransmitters in migraine.The journal of headache and pain · 2025Review
- GPe Projections to the Retrorubral Field Give Rise to Diverging GABAergic and DAergic Circuits.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Placebo and nocebo effect in pain.Handbook of clinical neurology · 2025Review
- Potential hypothalamic mechanisms in trigeminal neuropathic pain: a comparative analysis with migraine and cluster headache.The journal of headache and pain · 2024Review
- Uncovering the brain-wide pattern of synaptic input to vasopressin-expressing neurons in the paraventricular nucleus of the hypothalamus.The Journal of comparative neurology · 2023Article
- The Role of The Rostral Ventromedial Medulla in Stress Responses.Brain sciences · 2023Review
- Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters.Frontiers in pharmacology · 2023Review
- Shifting the Balance: How Top-Down and Bottom-Up Input Modulate PainFrontiers in pain research (Lausanne, Switzerland) · 2022Review
- Structural and functional connectivity from the dorsomedial hypothalamus to the ventral medulla as a chronological amplifier of sympathetic outflow.Scientific reports · 2020Article
- Descending Control Mechanisms and Chronic Pain.Current rheumatology reports · 2019Review
- Cholecystokinin Switches the Plasticity of GABA Synapses in the Dorsomedial Hypothalamus via Astrocytic ATP Release.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Corticotropin-Releasing Factor in the Brain and Blocking Spinal Descending Signals Induce Hyperalgesia in the Latent Sensitization Model of Chronic Pain.Neuroscience · 2018Article
- Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Narcotic bowel syndrome and opioid-induced constipation.Current gastroenterology reports · 2014Review
- Article
- CCK2 receptors in chronic pain.Neurobiology of pain (Cambridge, Mass.)Review
- Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK2 receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.