Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress.
OBJECTIVE
Chronic psychological stress is associated with visceral hyperalgesia and increased expression of spinal NK1 receptors (NK1Rs). We aimed to identify the role of spinal microglia in this process.


METHODS
Male Wistar rats were exposed to water avoidance (WA) or sham stress 1 hour each day for 10 days and given daily injections of minocycline, the p38 inhibitor SB203580, or saline. Phosphorylation levels of the kinase p38 (P-p38), the microglia marker OX42, NK1R, and IkappaBalpha were assessed by immunoblotting and/or immunostaining of spinal samples collected at day 11. The visceromotor response to colorectal distention at baseline and following WA were also assayed in rats given injections of minocycline, SB203580, or vehicle. The effects of fractalkine were assessed on the visceromotor response in rats exposed to minocycline or vehicle.


RESULTS
P-p38 protein levels and immunoreactivity were increased in stressed rats and colocalized with OX42-positive cells and neurons in the dorsal horn. This increase was reversed by minocycline or SB203580 exposure. Stress-induced increased NK1R expression was blocked by minocycline but not SB203580. WA-induced decreased IkappaBalpha expression was blocked by minocycline and SB203580. WA-induced hyperalgesia was blocked by minocycline and SB203580 intrathecally. Fractalkine-induced hyperalgesia was blocked by minocycline.


CONCLUSIONS
This is the first demonstration that stress-induced activation of spinal microglia has a key role in visceral hyperalgesia and associated spinal NK1R up-regulation.
Bradesi
Sylvie
S
Center for Neurobiology of Stress, Department of Medicine, University of California, Los Angeles, Los Angeles, California 90073, USA. sbradesi@ucla.edu
Svensson
Camilla I
CI
Steinauer
Joanne
J
Pothoulakis
Charalabos
C
Yaksh
Tony L
TL
Mayer
Emeran A
EA
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D013127:Spinal Nerves / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D014781:Viscera / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D014868:Water Deprivation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D018040:Receptors, Neurokinin-1; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline; C093642:SB 203580