Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli.
Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect.
Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland Physiology, School of Medicine, National University of Ireland, Galway, Ireland NCBES Galway Neuroscience Centre and Centre for Pain Research, National University of Ireland, Galway, Ireland.
Kieran
K
Rea
Weredeselam M
WM
Olango
Bright N
BN
Okine
Manish K
MK
Madasu
Iseult C
IC
McGuire
Kathleen
K
Coyle
Brendan
B
Harhen
Michelle
M
Roche
David P
DP
Finn
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D003863:Depression / Q000523:psychology*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism*; D005557:Formaldehyde / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006948:Hyperkinesis / Q000523:psychology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D042282:Microdissection; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D011897:Random Allocation; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D005557:Formaldehyde
Affect; Anandamide; Cannabinoid(1) (CB(1)) receptor; Fatty acid amide hydrolase (FAAH); Formalin; Pain; Rostroventromedial medulla (RVM); Wistar–Kyoto rat