Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P.
OBJECTIVE
Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis).


METHODS
The neural contractile response to electrical field stimulation of longitudinal muscle strips from the colon of patients undergoing surgery for colonic cancer or diverticulitis was challenged by different receptor agonists and antagonists.


RESULTS
Contractions of colonic strips from healthy controls and diverticulitis specimens were abolished by atropine. The beta adrenergic agonist (-) isoprenaline and the tachykinin NK1 receptor antagonist SR140333 had similar potency in reducing the electrical twitch response in controls and diseased tissues, while the cannabinoid receptor agonist (+)WIN 55,212-2 was 100 times more potent in inhibiting contractions in controls (IC50 42 nmol/l) than in diverticulitis strips. SR141716, a selective antagonist of the cannabinoid CB1 receptor, had no intrinsic activity in control preparations but potentiated the neural twitch in diseased tissues by up to 196% in a concentration dependent manner. SR141716 inhibited (+)WIN 55,212-2 induced relaxation in control strips but had no efficacy on (+)WIN 55,212-2 responses in strips from diverticular disease patients. Colonic levels of the endogenous ligand of cannabinoid and vanilloid TRPV1 receptors anandamide were more than twice those of control tissues (54 v 27 pmol/g tissue). The axonal conduction blocker tetrodotoxin had opposite effects in the two preparations, completely inhibiting the contractions of control strips but potentiating those in diverticular preparations, an effect selectively inhibited by SR140333.


CONCLUSIONS
Neural control of colon motility is profoundly altered in patients with diverticulitis. Their raised levels of anandamide, apparent desensitisation of the presynaptic neural cannabinoid CB1 receptor, and the SR141716 induced intrinsic response, suggest that endocannabinoids may be involved in the pathophysiology of complications of colonic diverticular disease.
Guagnini
F
F
Sanofi-Midy Research Centre, Sanofi-Aventis, Via GB Piranesi 38, 20137 Milan, Italy.
Valenti
M
M
Mukenge
S
S
Matias
I
I
Bianchetti
A
A
Di Palo
S
S
Ferla
G
G
Di Marzo
V
V
Croci
T
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D001095:Arachidonic Acids / Q000032:analysis / Q000378:metabolism; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D016022:Case-Control Studies; D003106:Colon / Q000503:physiopathology*; D004240:Diverticulum / Q000378:metabolism / Q000503:physiopathology*; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000294:innervation* / Q000503:physiopathology; D009281:Naphthalenes / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011412:Propanolamines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D000077285:Rimonabant; D013373:Substance P / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D007093:Imidazoles; D009025:Morpholines; D009281:Naphthalenes; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011412:Propanolamines; D011720:Pyrazoles; D011812:Quinuclidines; C085215:SR 140333; D013373:Substance P; D013779:Tetrodotoxin; C026777:ICI 118551; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; C049763:CGP 20712A; D007545:Isoproterenol; D000077285:Rimonabant; C078814:anandamide