Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine

Roger Guy Pertwee, S R Fernando, J E Nash, Angela Alice Coutts

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

1 CP 50,556, CP 55,940, nabilone, CP 56,667, Delta(9)-tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.36, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [H-3]-CP 55,940 from cannabinoid binding sites.

2 Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50=1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens.

3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 mu M) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine.

4 Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2.

5 Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 mu M SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940.

6 These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine.

7 THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor.

8 At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.

Original languageEnglish
Pages (from-to)2199-2205
Number of pages7
JournalBritish Journal of Pharmacology
Volume118
Issue number8
Publication statusPublished - Aug 1996

Keywords

  • myenteric plexus
  • guinea-pig small intestine
  • acetylcholine release
  • cannabinoid receptor agonists
  • cannabinoid receptor antagonist
  • Delta 9-tetrahydrocannabinol
  • AM 630
  • SR141716A
  • VAS-DEFERENS
  • BRAIN
  • ANTAGONIST
  • BINDS
  • delta 9-tetrahydrocannabinol

Cite this

Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. / Pertwee, Roger Guy; Fernando, S R ; Nash, J E ; Coutts, Angela Alice.

In: British Journal of Pharmacology, Vol. 118, No. 8, 08.1996, p. 2199-2205.

Research output: Contribution to journalArticle

Pertwee, Roger Guy ; Fernando, S R ; Nash, J E ; Coutts, Angela Alice. / Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. In: British Journal of Pharmacology. 1996 ; Vol. 118, No. 8. pp. 2199-2205.
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T1 - Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine

AU - Pertwee, Roger Guy

AU - Fernando, S R

AU - Nash, J E

AU - Coutts, Angela Alice

PY - 1996/8

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N2 - 1 CP 50,556, CP 55,940, nabilone, CP 56,667, Delta(9)-tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.36, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [H-3]-CP 55,940 from cannabinoid binding sites.2 Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50=1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens.3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 mu M) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine.4 Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2.5 Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 mu M SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940.6 These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine.7 THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor.8 At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.

AB - 1 CP 50,556, CP 55,940, nabilone, CP 56,667, Delta(9)-tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.36, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [H-3]-CP 55,940 from cannabinoid binding sites.2 Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50=1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens.3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 mu M) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine.4 Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2.5 Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 mu M SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940.6 These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine.7 THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor.8 At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.

KW - myenteric plexus

KW - guinea-pig small intestine

KW - acetylcholine release

KW - cannabinoid receptor agonists

KW - cannabinoid receptor antagonist

KW - Delta 9-tetrahydrocannabinol

KW - AM 630

KW - SR141716A

KW - VAS-DEFERENS

KW - BRAIN

KW - ANTAGONIST

KW - BINDS

KW - delta 9-tetrahydrocannabinol

M3 - Article

VL - 118

SP - 2199

EP - 2205

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8

ER -