title: The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.
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.
authors: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA.
authors: K M
authors: KM
authors: Wagner
authors: Z
authors: Z
authors: Roeder
authors: K
authors: K
authors: Desrochers
authors: A V
authors: AV
authors: Buhler
authors: M M
authors: MM
authors: Heinricher
authors: D R
authors: DR
authors: Cleary
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism*; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D006727:Hormone Antagonists; D043887:Receptor, Cholecystokinin B; D001569:Benzodiazepines; C087260:YM 022; D002766:Cholecystokinin