or 2010?nmol?mouse?1, i.p.) after both we.c.v. SR141716A (16?nmol?mouse?1, i.p.) however, not by SR144528 (52?nmol?mouse?1, i.p.) both in croton-oil and control treated mice. Ganglionic blockade with hexamethonium (69?nmol?mouse?1, i.p.) didn’t enhance the inhibitory aftereffect of we.p.-injected cannabinoid agonists either in charge or in croton-oil treated mice. The low ED50 beliefs of cannabinoid medications when i.c.v. administration recommend a central (CB1) site of actions. Nevertheless, a peripheral site of actions is recommended by having less aftereffect of hexamethonium. Furthermore, croton oil-induced diarrhoea enhances the result of cannabinoid agonists with a peripheral system. have been utilized medicinally for more than 4000 years for the treating a number of Razaxaban disorders, including migraine, muscles spasm, seizures, glaucoma, discomfort, nausea and diarrhoea (Felder & Cup, 1998). In 1964 9-tetrahydrocannabinol (9-THC) was isolated, that was later been shown to be responsible for lots of the pharmacological activities of arrangements (Mechoulam matching control. Desk 1 ED50s.e.mean and Emaxs.e.mean of cannabinoid medications when i.p. or i.c.v. administration in charge mice and in mice getting croton essential oil (0.01?ml mouse?1, orally) Open up in another screen The CB1 receptor antagonist SR141716A (16?nmol mouse?1, i.p.), however, not the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) counteracted the inhibitory aftereffect of Gain 55,212-2 (5?nmol?mouse?1, i.c.v. or 50?nmol?mouse?1, i.p.) and cannabinol (201?nmol?mouse?1, i.c.v. or 2010?nmol?mouse?1, i.p.) after both we.c.v. (Body 2) and i.p. (Body 3) routes of administration. Hexamethonium (69?nmol?mouse?1, i.p.) abolished the result of both WIN 55,212-2 and cannabinol when i.c.v. (Body 2) however, not when i.p. (Body 3) administration. Open up in another window Body 2 Aftereffect of WIN 55,212-2 (5?nmol?mouse?1 we.c.v) and cannabinol (201?nmol?mouse, we.c.v.) on higher gastrointestinal transit by itself or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol mouse?1, i.p.). Email address details are means.e.mean of 8C11 pets for every experimental group. *control and #WIN 55,212-2 (or cannabinol). Open up in another window Body 3 Aftereffect of WIN 55,212-2 (50?nmol?mouse?1, i.p.) and cannabinol (2010?nmol?mouse?1, i.p.) on higher gastrointestinal transit by itself or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Email address details are means.e.mean of 8C11 pets for every experimental group. **control and #WIN 55,212-2 (or cannabinol). SR 14176A (i.p. or i.c.v.), matching control. The CB2 receptor antagonist SR144528 (52?nmol mouse?1, i.p.), provided alone, didn’t significantly enhance gastrointestinal transit (control 474%; SR144528 482%, matching control. Implemented i.c.v. WIN 55,212-2 (2C239?nmol?mouse?1) also decreased intestinal motility, however the ED50 worth (7410?nmol?mouse?1) had not been statistically not the same as the ED50 worth (685?nmol?mouse?1) when i.p. administration (Desk 1). The inhibitory aftereffect of i.p.-injected WIN 55,212-2 (14?nmol?mouse?1) or cannabinol (805?nmol?mouse?1) was reduced by the CB1 receptor antagonist SR141716A (16?nmol?mouse?1, i.p.) but not by the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) or by the ganglion blocker hexamethonium (69?nmol?mouse?1, i.p.) (Physique 6). Open in a separate window Physique 6 Upper gastrointestinal transit in mice with diarrhoea induced by croton oil (0.01?ml?mouse?1, orally): effect of WIN 55,212-2 (14?nmol?mouse?1, i.p.) and cannabinol (805?nmol mouse?1, i.p.) alone or in mice treated with SR141716A (16?nmol mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. @control, **croton oil and #croton oil+WIN 55,212-2 (or croton oil+cannabinol). Physique 4b shows the potentiating effect of SR141716A (2C539?nmol?mouse, i.p.) in mice treated with croton oil. The ED50 value (41832?nmol?mouse?1) was not statistically different from the corresponding ED50 value in control animals (37531?nmol?mouse?1). By contrast, SR144528 (52?nmol mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.) did not change gastrointestinal transit (per cent transit: croton oil: 586, croton oil+SR144528 615, croton oil+hexamethonium 684, findings, it has been shown that cannabinoid agonists reduced intestinal motility in mice (Calignano is usually mediated a central or a peripheral site of action was not exhibited in these studies. Indeed the CB1 receptor is located within.In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism. have been used medicinally for over 4000 years for the treatment of a variety of disorders, including migraine, muscle spasm, seizures, glaucoma, pain, nausea and diarrhoea (Felder & Glass, 1998). Ganglionic blockade with hexamethonium (69?nmol?mouse?1, i.p.) did not change the inhibitory effect of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB1) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism. have been used medicinally for over 4000 years for the treatment of a variety of disorders, including migraine, muscle spasm, seizures, glaucoma, pain, nausea and diarrhoea (Felder & Glass, 1998). In 1964 9-tetrahydrocannabinol (9-THC) was isolated, which was later shown to be responsible for many of the pharmacological actions of preparations (Mechoulam corresponding control. Table 1 ED50s.e.mean and Emaxs.e.mean of cannabinoid drugs after i.p. or i.c.v. administration in control mice and in mice receiving croton oil (0.01?ml mouse?1, orally) Open in a separate window The CB1 receptor antagonist SR141716A (16?nmol mouse?1, i.p.), but not the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) counteracted the inhibitory effect of WIN 55,212-2 (5?nmol?mouse?1, i.c.v. or 50?nmol?mouse?1, i.p.) and cannabinol (201?nmol?mouse?1, i.c.v. or 2010?nmol?mouse?1, i.p.) after both i.c.v. (Physique 2) and i.p. (Physique 3) routes of administration. Hexamethonium (69?nmol?mouse?1, i.p.) abolished the effect of both WIN 55,212-2 and cannabinol after i.c.v. (Physique 2) but not after i.p. (Physique 3) administration. Open in Razaxaban a separate window Physique 2 Effect of WIN 55,212-2 (5?nmol?mouse?1 i.c.v) and cannabinol (201?nmol?mouse, i.c.v.) on upper gastrointestinal transit alone or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. *control and #WIN 55,212-2 (or cannabinol). Open in a separate window Physique 3 Effect of WIN 55,212-2 (50?nmol?mouse?1, i.p.) and cannabinol (2010?nmol?mouse?1, i.p.) on upper gastrointestinal transit alone or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. **control and #WIN 55,212-2 (or cannabinol). SR 14176A (i.p. or i.c.v.), corresponding control. The CB2 receptor antagonist SR144528 (52?nmol mouse?1, i.p.), given alone, did not significantly change gastrointestinal transit (control 474%; SR144528 482%, corresponding control. Administered i.c.v. WIN 55,212-2 (2C239?nmol?mouse?1) also decreased intestinal motility, but the ED50 value (7410?nmol?mouse?1) was not statistically different from the ED50 value (685?nmol?mouse?1) after i.p. administration (Table 1). The inhibitory effect of i.p.-injected WIN 55,212-2 (14?nmol?mouse?1) or cannabinol (805?nmol?mouse?1) was reduced by the CB1 receptor antagonist SR141716A (16?nmol?mouse?1, i.p.) but not by the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) or by the ganglion blocker hexamethonium (69?nmol?mouse?1, i.p.) (Physique 6). Open in a separate window Physique 6 Upper gastrointestinal transit in mice with diarrhoea induced by croton oil (0.01?ml?mouse?1, orally): effect of WIN 55,212-2 (14?nmol?mouse?1, i.p.) and cannabinol (805?nmol mouse?1, i.p.) alone or in mice treated with SR141716A (16?nmol mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. @control, **croton oil and #croton oil+WIN 55,212-2 (or croton oil+cannabinol). Physique 4b shows the potentiating effect of SR141716A (2C539?nmol?mouse, i.p.) in mice treated with croton oil. The ED50 value (41832?nmol?mouse?1) was not statistically different from the corresponding ED50 value in control animals (37531?nmol?mouse?1). By contrast, SR144528 (52?nmol mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.) did not change gastrointestinal transit (per cent transit: croton oil: 586, croton oil+SR144528 615, croton oil+hexamethonium 684, findings, it has been shown that cannabinoid agonists reduced intestinal motility in mice (Calignano is usually mediated a central or a peripheral site of action was not exhibited in these studies. Indeed the CB1 receptor is located within both the central nervous system (Matsuda croton oil), different species (rat mouse) and different region of the gut (whole gut upper gastrointestinal tract) could explain this discrepancy. Consistent with this hypothesis, Shook & Burks (1989) showed that 9-THC produced a greater inhibition of small intestinal transit than large bowel transit. In line with the result obtained in control mice and those reported in the isolated guinea-pig ileum (Pertwee and Enrico and Enrica Sovena Foundation (Roma). The Authors are grateful to Drs Antonio Calignano and Carla Cicala for their help. SR141716A and SR144528 were a kind gift from SANOFI (Montpellier, France). Abbreviations COcroton oil9-THC9-tetrahydrocannabinol.SR141716A and SR144528 were a kind gift from SANOFI (Montpellier, France). Abbreviations COcroton oil9-THC9-tetrahydrocannabinol. (69?nmol?mouse?1, i.p.) did not modify the inhibitory effect of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB1) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism. have been used medicinally for over 4000 years for the treatment of a variety of disorders, including migraine, muscle spasm, seizures, glaucoma, pain, nausea and diarrhoea (Felder & Glass, 1998). NEK3 In 1964 9-tetrahydrocannabinol (9-THC) was isolated, which was later shown to be responsible for many of the pharmacological actions of preparations (Mechoulam corresponding control. Table 1 ED50s.e.mean and Emaxs.e.mean of cannabinoid drugs after i.p. or i.c.v. administration in control mice and in mice receiving croton oil (0.01?ml mouse?1, orally) Open in a separate window The CB1 receptor antagonist SR141716A (16?nmol mouse?1, i.p.), but not the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) counteracted the inhibitory effect of WIN 55,212-2 (5?nmol?mouse?1, i.c.v. or 50?nmol?mouse?1, i.p.) and cannabinol (201?nmol?mouse?1, i.c.v. or 2010?nmol?mouse?1, i.p.) after both i.c.v. (Figure 2) and i.p. (Figure 3) routes of administration. Hexamethonium (69?nmol?mouse?1, i.p.) abolished the effect of both WIN 55,212-2 and cannabinol after i.c.v. (Figure 2) but not after i.p. (Figure 3) administration. Open in a separate window Figure 2 Effect of WIN 55,212-2 (5?nmol?mouse?1 i.c.v) and cannabinol (201?nmol?mouse, i.c.v.) on upper gastrointestinal transit alone or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. *control and #WIN 55,212-2 (or cannabinol). Open in a separate window Figure 3 Effect of WIN 55,212-2 (50?nmol?mouse?1, i.p.) and cannabinol (2010?nmol?mouse?1, i.p.) on upper gastrointestinal transit alone or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. **control and #WIN 55,212-2 (or cannabinol). SR 14176A (i.p. or i.c.v.), corresponding control. The CB2 receptor antagonist SR144528 (52?nmol mouse?1, i.p.), given alone, did not significantly modify gastrointestinal transit (control 474%; SR144528 482%, corresponding control. Administered i.c.v. WIN 55,212-2 (2C239?nmol?mouse?1) also decreased intestinal motility, but the ED50 value (7410?nmol?mouse?1) was not statistically different from the ED50 value (685?nmol?mouse?1) after i.p. administration (Table 1). The inhibitory effect of i.p.-injected WIN 55,212-2 (14?nmol?mouse?1) or cannabinol (805?nmol?mouse?1) was reduced by the CB1 receptor antagonist SR141716A (16?nmol?mouse?1, i.p.) but not by the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) or by the ganglion blocker hexamethonium (69?nmol?mouse?1, i.p.) (Figure 6). Open in a separate window Figure 6 Upper gastrointestinal transit in mice with diarrhoea induced by croton oil (0.01?ml?mouse?1, orally): effect of WIN 55,212-2 (14?nmol?mouse?1, i.p.) and cannabinol (805?nmol mouse?1, i.p.) alone or in mice treated with SR141716A (16?nmol mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. @control, **croton oil and #croton oil+WIN 55,212-2 (or croton oil+cannabinol). Figure 4b shows the potentiating effect of SR141716A (2C539?nmol?mouse, i.p.) in mice treated with croton oil. The ED50 value (41832?nmol?mouse?1) was not statistically different from the corresponding ED50 value in control animals (37531?nmol?mouse?1). By contrast, SR144528 (52?nmol mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.) did not modify gastrointestinal transit (per cent transit: croton oil: 586, croton oil+SR144528 615, croton oil+hexamethonium 684, findings, it has been shown that cannabinoid agonists reduced intestinal motility in mice (Calignano is mediated a central or a peripheral site of action was not demonstrated in these studies. Indeed the CB1 receptor is located within both the central nervous system (Matsuda croton oil), Razaxaban different species (rat mouse) and different region of the gut (whole gut upper gastrointestinal tract) could explain this discrepancy. Consistent with this hypothesis, Shook & Burks (1989) showed that 9-THC produced a greater inhibition of small intestinal transit than large bowel transit. In line with the result obtained in control.**control and #WIN 55,212-2 (or cannabinol). SR 14176A (i.p. i.p. or i.c.v. administration. The inhibitory effects of WIN 55,212-2 and cannabinol were counteracted by SR141716A (16?nmol?mouse?1, i.p.) but not by SR144528 (52?nmol?mouse?1, i.p.) both in control and croton-oil treated mice. Ganglionic blockade with hexamethonium (69?nmol?mouse?1, i.p.) did not modify the inhibitory effect Razaxaban of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB1) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism. have been used medicinally for over 4000 years for the treatment of a variety of disorders, including migraine, muscle spasm, seizures, glaucoma, pain, nausea and diarrhoea (Felder & Glass, 1998). In 1964 9-tetrahydrocannabinol (9-THC) was isolated, which was later shown to be responsible for many of the pharmacological actions of preparations (Mechoulam corresponding control. Table 1 ED50s.e.mean and Emaxs.e.mean of cannabinoid drugs after i.p. or i.c.v. administration in control mice and in mice receiving croton oil (0.01?ml mouse?1, orally) Open in a separate windows The CB1 receptor antagonist SR141716A (16?nmol mouse?1, i.p.), but not the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) counteracted the inhibitory effect of Get 55,212-2 (5?nmol?mouse?1, i.c.v. or 50?nmol?mouse?1, i.p.) and cannabinol (201?nmol?mouse?1, i.c.v. or 2010?nmol?mouse?1, i.p.) after both i.c.v. (Number 2) and i.p. (Number 3) routes of administration. Hexamethonium (69?nmol?mouse?1, i.p.) abolished the effect of both WIN 55,212-2 and cannabinol after i.c.v. (Number 2) but not after i.p. (Number 3) administration. Open in a separate window Number 2 Effect of WIN 55,212-2 (5?nmol?mouse?1 i.c.v) and cannabinol (201?nmol?mouse, i.c.v.) on top gastrointestinal transit only or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. *control and #WIN 55,212-2 (or cannabinol). Open in a separate window Number 3 Effect of WIN 55,212-2 (50?nmol?mouse?1, i.p.) and cannabinol (2010?nmol?mouse?1, i.p.) on top gastrointestinal transit only or in mice treated with SR141716A (16?nmol?mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. **control and #WIN 55,212-2 (or cannabinol). SR 14176A (i.p. or i.c.v.), related control. The CB2 receptor antagonist SR144528 (52?nmol mouse?1, i.p.), given alone, did not significantly improve gastrointestinal transit (control 474%; SR144528 482%, related control. Given i.c.v. WIN 55,212-2 (2C239?nmol?mouse?1) also decreased intestinal motility, but the ED50 value (7410?nmol?mouse?1) was not statistically different from the ED50 value (685?nmol?mouse?1) after i.p. administration (Table 1). The inhibitory effect of i.p.-injected WIN 55,212-2 (14?nmol?mouse?1) or cannabinol (805?nmol?mouse?1) was reduced from the CB1 receptor antagonist SR141716A (16?nmol?mouse?1, i.p.) but not from the CB2 receptor antagonist SR144528 (52?nmol?mouse?1, i.p.) or from the ganglion blocker hexamethonium (69?nmol?mouse?1, i.p.) (Number 6). Open in a separate window Number 6 Upper gastrointestinal transit in mice with diarrhoea induced by croton oil (0.01?ml?mouse?1, orally): effect of Get 55,212-2 (14?nmol?mouse?1, i.p.) and cannabinol (805?nmol mouse?1, i.p.) only or in mice treated with SR141716A (16?nmol mouse?1, i.p.) or SR144528 (52?nmol?mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.). Results are means.e.mean of 8C11 animals for each experimental group. @control, **croton oil and #croton oil+WIN 55,212-2 (or croton oil+cannabinol). Number 4b shows the potentiating effect of SR141716A (2C539?nmol?mouse, i.p.) in mice treated with croton oil. The ED50 value (41832?nmol?mouse?1) was not statistically different from the corresponding ED50 value in control animals (37531?nmol?mouse?1). By contrast, SR144528 (52?nmol mouse?1, i.p.) or hexamethonium (69?nmol?mouse?1, i.p.) did not improve gastrointestinal transit (per cent transit: croton oil: 586, croton oil+SR144528 615, croton oil+hexamethonium 684, findings, it has been demonstrated that cannabinoid agonists reduced intestinal motility in mice (Calignano is definitely mediated a central or a peripheral site of action was not shown in these studies. Indeed the CB1 receptor is located within both the central nervous system (Matsuda croton oil), different varieties (rat mouse) and different region of the gut (whole gut top gastrointestinal tract) could clarify this discrepancy. Consistent with this hypothesis, Shook & Burks (1989) showed that 9-THC produced a greater inhibition of small intestinal transit than large bowel transit. Good result obtained in control mice and those reported in the isolated guinea-pig ileum (Pertwee and Enrico and Enrica Sovena Basis.