title: Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats.
abstract: 1. The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the rostral ventrolateral medulla oblongata (RVLM) affects cardiovascular and/or respiratory function. 2. Initially, we looked for evidence of CB1 receptor gene expression in rostral and caudal sections of the rat ventrolateral medulla (VLM) using reverse transcription-polymerase chain reaction. Second, the potent cannabinoid receptor agonists WIN55,212-2 (0.05, 0.5 or 5 pmol per 50 nl) and HU-210 (0.5 pmol per 50 nl) or the CB1 receptor antagonist/inverse agonist AM281 (1 pmol per 100 nl) were microinjected into the RVLM of urethane-anaesthetised, immobilised and mechanically ventilated male Sprague-Dawley rats (n=22). Changes in splanchnic nerve activity (sSNA), phrenic nerve activity (PNA), mean arterial pressure (MAP) and heart rate (HR) in response to cannabinoid administration were recorded. 3. The CB1 receptor gene was expressed throughout the VLM. Unilateral microinjection of WIN55,212-2 into the RVLM evoked short-latency, dose-dependent increases in sSNA (0.5 pmol; 175+/-8%, n=5) and MAP (0.5 pmol; 26+/-3%, n=8) and abolished PNA (0.5 pmol; duration of apnoea: 5.4+/-0.4 s, n=8), with little change in HR (P<0.005). HU-210, structurally related to Delta9-tetrahydrocannabinol (THC), evoked similar effects when microinjected into the RVLM (n=4). Surprisingly, prior microinjection of AM281 produced agonist-like effects, as well as significantly attenuated the response to subsequent injection of WIN55,212-2 (0.5 pmol, n=4). 4. The present study reveals CB1 receptor gene expression in the rat VLM and demonstrates sympathoexcitation, hypertension and respiratory inhibition in response to RVLM-administered cannabinoids. These findings suggest a novel link between CB1 receptors in this region of the hindbrain and the central cardiorespiratory effects of cannabinoids. The extent to which these central effects contribute to the cardiovascular and respiratory outcomes of cannabis use remains to be investigated.
authors.affiliation: Hypertension and Stroke Research Laboratories, Department of Neurosurgery, Ground Floor Block 3, Royal North Shore Hospital, St Leonards 2065, NSW, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Padley
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Paul M
authors.initials: PM
authors.lastname: Pilowsky
authors.forename: Ann K
authors.initials: AK
authors.lastname: Goodchild
mesh_terms: D000758:Anesthesia; D000818:Animals; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013153:Splanchnic Nerves / Q000187:drug effects / Q000502:physiology
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D018696:Neuroprotective Agents; D011720:Pyrazoles; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C062018:HU 211; C109925:AM 281