Investigation on the relationship between cannabinoid CB1 and opioid receptors in gastrointestinal motility in mice

Abstract

1. This study investigated whether (a) cannabinoid CB(1) receptor knockout (CB(1)(-/-)) mice displayed altered gastrointestinal transit and (b) cannabinoid CB(1) and opioid receptors functionally interact in the regulation of gastrointestinal transit. 2. Gastrointestinal transit was assessed by the Whole Gastrointestinal Transit, measuring the excretion time of an intragastrically administered marker (whole intestine), and the Upper Gastrointestinal Transit, measuring the distance covered by the marker in the small intestine. 3. CB(1)(-/-) and homozygous CB(1)(+/+) (CB(1)(+/+)) mice did not differ in both whole gut and small intestine transit. CB(1)(-/-) and CB(1)(+/+) mice were equally responsive to the inhibitory effect of morphine (10 mg kg(-1)) and loperamide (3 mg kg(-1)) on whole gut transit.4. Additionally, in CD1 mice the cannabinoid CB(1) receptor antagonist, rimonabant (0-0.5 mg kg(-1)), failed to block the inhibitory effect of morphine (0-1.25 mg kg(-1)) and loperamide (0-0.5 mg kg(-1)) on transit in small and whole intestine. Similarly, the opioid receptor antagonists, naloxone (0-1 mg kg(-1)) and naltrexone (0-10 mg kg(-1)), failed to block the inhibitory effect of the cannabinoid WIN 55,212-2 (0-3 mg kg(-1)) on transit in small and whole intestine.5. These results suggest that (a) compensatory mechanisms likely developed in CB(1)(-/-) mice to overcome the lack of inhibitory function of endocannabinoid system; (b) cannabinoid and opioid receptor systems did not interact in regulating gastrointestinal transit in mice.

Figure 1

Effect of the acute, intraperitoneal administration of different doses of the cannabinoid, WIN 55,212-2 (a), morphine (b), and loperamide (c) on time of whole gut transit in propulsive activity in CB₁^−/− and CB₁^+/+ mice. Time of whole gut transit indicated the time elapsing between the intragastric administration of the nonabsorbable coloured marker, carmine, and excretion of the first red fecal bolus. Each bar is the mean±s.e.m. of n=6–8 mice. ^*P<0.05 with respect to vehicle-treated mice of the same strain (Newman–Keuls test).

Figure 2

Distance travelled in the small intestine by the head of the nonabsorbable coloured marker, carmine, administered intragastrically to undrugged CB₁^−/− and CB₁^+/+ mice 20 min before the killing. Distance travelled was expressed as percent of total length of the small intestine. Each bar is the mean±s.e.m. of n=10 mice.

Figure 3

Effect of the acute, intraperitoneal administration of rimonabant on the increase in time of whole gut transit induced by the acute, intraperitoneal administration of WIN 55,212-2 (a), morphine (b), and loperamide (c) in CD1 mice. Time of whole gut transit indicated the time elapsing between the intragastric administration of the nonabsorbable coloured marker, carmine, and excretion of the first red fecal bolus. Each bar is the mean±s.e.m. of n=10 mice. ^*P<0.05 with respect to: 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (b); 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (c). +: P<0.05 with respect to 0 mg kg⁻¹ rimonabant plus 3 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (a).

Figure 4

Effect of the acute, intraperitoneal administration of naltrexone on the increase in time of whole gut transit induced by the acute, intraperitoneal administration of morphine (a), loperamide (b), and WIN 55,212-2 (c) in CD1 mice. Time of whole gut transit indicated the time elapsing between the intragastric administration of the nonabsorbable coloured marker, carmine, and excretion of the first red fecal bolus. Each bar is the mean±s.e.m. of n=10 mice. ^*P<0.05 with respect to: 0 mg kg⁻¹ naltrexone plus 0 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ naltrexone plus 0 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (b); 0 mg kg⁻¹ naltrexone plus 0 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (c). +: P<0.05 with respect to: 0 mg kg⁻¹ naltrexone plus 10 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ naltrexone plus 3 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (b).

Figure 5

Effect of the acute, intraperitoneal administration of rimonabant on the decrease, induced by the acute, intraperitoneal administration of WIN 55,212-2 (a), morphine (b), and loperamide (c), in the distance travelled in the small intestine by the head of the nonabsorbable coloured marker, carmine, in CD1 mice. Mice were killed 20 min after carmine administration. Distance travelled was expressed as percent of total length of the small intestine. Each bar is the mean±s.e.m. of n=10 mice. ^*P<0.05 with respect to: 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (b); 0 mg kg⁻¹ rimonabant plus 0 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (c). +: P<0.05 with respect to 0 mg kg⁻¹ rimonabant plus 0.5 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (a).

Figure 6

Effect of the acute, intraperitoneal administration of naloxone on the decrease, induced by the acute, intraperitoneal administration of morphine (a), loperamide (b), and WIN 55,212-2 (c), in the distance travelled in the small intestine by the head of the nonabsorbable coloured marker, carmine, in CD1 mice. Mice were killed 20 min after carmine administration. Distance travelled was expressed as percent of total length of the small intestine. Each bar is the mean±s.e.m. of n=10 mice. ^*P<0.05 with respect to: 0 mg kg⁻¹ naloxone plus 0 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ naloxone plus 0 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (b); 0 mg kg⁻¹ naloxone plus 0 mg kg⁻¹ WIN 55,212-2-treated mice (Newman–Keuls test) in (c). +: P<0.05 with respect to: 0 mg kg⁻¹ naloxone plus 1.25 mg kg⁻¹ morphine-treated mice (Newman–Keuls test) in (a); 0 mg kg⁻¹ naloxone plus 0.5 mg kg⁻¹ loperamide-treated mice (Newman–Keuls test) in (b).