Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli

• Published in: Pain (Amsterdam) Vol. 155; no. 1; pp. 69 - 79
• Main Authors: Rea, Kieran, Olango, Weredeselam M., Okine, Bright N., Madasu, Manish K., McGuire, Iseult C., Coyle, Kathleen, Harhen, Brendan, Roche, Michelle, Finn, David P.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.01.2014; International Association for the Study of Pain; Elsevier
• Subjects: Affect; Anandamide; Animals; Biological and medical sciences; Cannabinoid Receptor Modulators - pharmacology; Cannabinoid1 (CB1) receptor; Depression - psychology; Disease Models, Animal; Endocannabinoids - genetics; Endocannabinoids - metabolism; Fatty acid amide hydrolase (FAAH); Formaldehyde - toxicity; Formalin; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Hyperkinesis - psychology; Male; Medical sciences; Medulla Oblongata - drug effects; Medulla Oblongata - metabolism; Microdissection; Neuropharmacology; Nociception - drug effects; Nociception - physiology; Pain; Pain Measurement; Pharmacology. Drug treatments; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Random Allocation; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - metabolism; Rostroventromedial medulla (RVM); Signal Transduction - drug effects; Signal Transduction - physiology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Vertebrates: nervous system and sense organs; Wistar–Kyoto rat; Pain; Fatty acid amide hydrolase (FAAH); Rostroventromedial medulla (RVM); Formalin; Cannabinoid1 (CB1) receptor; Affect; Wistar–Kyoto rat; Anandamide; CB1 cannabinoid receptor; Noxious stimulus; Rat; Lipids; Cannabinoid; Genetic determinism; Endocannabinoid; Wistar-Kyoto rat; Genetics; CB; Enzyme; Rodentia; Genotype; Fatty acids; Vertebrata; Mammalia; receptor; Animal; Hydrolases; Cannabinoid (CB) receptor
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1016/j.pain.2013.09.012

Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins hyper-responsivity to a noxious inflammatory stimulus in the Wistar–Kyoto rat, a genetic background prone to heightened stress/affect. 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.