Cannabinoid mediated diuresis in mice Doctoral Dissertation presented by Girish Rajmal Chopda on August 7 th 2013 To The Bouve’ Graduate School of Health Sciences in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in Pharmaceutical Sciences with specialization in Pharmacology Department of Pharmaceutical Sciences, Northeastern University, Boston, MA
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Cannabinoid mediated
diuresis in mice Doctoral Dissertation presented by
Girish Rajmal Chopda
on
August 7th
2013
To
The Bouve’ Graduate School of Health Sciences
in partial fulfillment of the requirements for the
Degree of Doctor of Philosophy in Pharmaceutical Sciences
with specialization in Pharmacology
Department of Pharmaceutical Sciences, Northeastern
University, Boston, MA
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
ii
Department of Pharmaceutical Sciences, Northeastern University, Doctoral Dissertation
Dissertation Title: Cannabinoid mediated diuresis in mice
Presented by: Girish Rajmal Chopda
Date to be presented: 7th August 2013
Thesis Committee:
Chair and Advisor Dr Carol A Paronis Approval date: _____________
Member Dr David Janero Approval date: _____________
Member Dr John Gatley Approval date: _____________
Member Dr Torbjorn Jarbe Approval date: _____________
Member Dr Jack Bergman Approval date: _____________
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
iii
I am dedicating my thesis to my father Rajmal I Chopda, my mother Sangeeta R
Chopda, my wife Aditee, my brother Vishal and my advisor Carol A Paronis.
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
iv
Table of Contents:
Page
Number
A. Abstract
1
B. Resources Available
2
C. Biographical Sketch
3
D. Specific Aims 5
Chapter 1 – Introduction and background to the cannabinoid system
1.1 – History
1.2 – Cannabinoid receptors
1.3 – Endocannabinoid system
1.4 – Endocannabinoid chemistry
1.5 – In vivo effects of cannabinoids
1.6 – Cannabinoids in clinical use
7
7
8
10
12
19
21
Chapter 2 – Cannabinoid mediated diuresis in mice
2.1 - Introduction
2.1.1 – Cannabinoid and diuresis
2.1.2 – Cannabinoid receptors in the urinary system
2.1.3 – Standard diuretics
2.2 – Aim and rationale
2.3 – Material and methods
2.3.1 – Animals
2.3.2 – Diuresis
2.3.3 – Measurement of urine pH, Na+, K
+ and Cl
-
2.3.4 – Drugs
2.3.5 – Statistical analysis
2.4 – Results
2.4.1 – Validating diuresis
2.4.2 – Cannabinoid mediated diuresis
2.4.3 – Receptor mechanisms of cannabinoid mediated diuresis
2.4.4 – Urine analysis
2.5 – Discussion
2.5.1 – Validation of diuresis
2.5.2 – Cannabinoid mediated diuresis
23
23
23
24
27
28
29
29
29
29
29
30
31
31
35
39
50
52
52
53
Chapter 3 - Cannabinoid mediated antinociception in mice
3.1 – Introduction
3.1.1 – Cannabinoid antinociception
3.2 – Aim and rationale
3.3 – Material and methods
3.3.1 – Animals
3.3.2 – Antinociception
3.3.3 – Drugs
3.3.4 – Statistical analysis
3.4 – Results
59
59
59
61
62
62
62
63
63
64
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
v
3.4.1 – Effects of cannabinoid agonists on antinociception
3.4.2Effects of antagonist pretreatment
3.5 – Discussion
Chapter 4 – Cannabinoid mediated tolerance
4.1 – Introduction
4.1.1 – Drug tolerance
4.1.2 – Cannabinoid and tolerance
4.2 – Aim and rationale
4.3 – Material and methods
4.3.1 – Animals
4.3.2 – Antinociception
4.3.3 – Diuresis
4.3.4 – Binding assay
4.3.5 – Drugs
4.3.6 – Statistical analysis
4.4 – Results
4.4.1 – Tolerance to diuresis
4.4.2 – Tolerance to antinociception
4.4.3 – Changes in CB1 receptor levels
4.5 – Discussion
E. Conclusions
64
72
78
82
82
82
82
85
86
86
86
86
87
87
88
89
89
93
97
99
103
F. Bibliography
107
G. Appendix: Laboratory Safety Training
115
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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A. Abstract: Cannabinoid receptor agonists increase urinary output in rats; however
these effects have not been characterized in mice. This study investigates whether diuresis is a
cannabinoid receptor mediated effect in mice, and further compares cannabinoid mediated
diuresis with antinociception. Adult male CD1 mice were injected sc (10 ml/kg) with vehicle or
novel and commercially available cannabinoid agonists [AM4054, AM7418, THC (∆9-
tetrahydrocannabinol) and WIN55212-22]. Voided urine was measured over 6 hr using single
dosing procedures. Antinociception was measured using cumulative dosing procedures and a
warm water (52oC) tail-withdrawal assay. In antagonism studies, cannabinoid CB1 receptor
hexahydrocannabinol] was synthesized at the Center for Drug Discovery, Northeastern
University. All compounds were prepared in 5% ethanol, 5% emulphor-620 (Rhodia, Cranbury,
NJ) and 90% saline, and further diluted with saline. Except where noted, injections were
delivered s.c. in volumes of 1ml/100g body weight; drug doses are expressed in terms of the
weight of free base.
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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4.3.6 Statistical analysis: Tail withdrawal latencies are expressed as a percentage of
maximum possible effect (%MPE), calculated using the formula: %MPE = [(test latency −
baseline latency)/ (8 − baseline latency)] × 100. To determine ED50values for diuresis, 50% of
the maximum effect was defined using the formula: [((maximum urine output with the drug –
urine output with vehicle)/2) + urine output with vehicle]. ED50 values were calculated using
linear regression when more than two data points were available, and otherwise were calculated
by interpolation. For binding studies, data were normalized to the protein content of the brain
homogenate and specific binding was determined by subtracting the non specific binding from
the total binding. Scatchard plot was used for determining Bmax values by extrapolating the
linear regression line on the x-axis.
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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4.4 Results:
4.4.1 Tolerance to diuresis: Similar to effects reported in Chapter 2, THC increased
urine output compared to vehicle treated animals, and doses higher than 10 mg/kg again formed
a descending limb of a biphasic dose-effect function. Tolerance to the diuretic effects of 10.0
mg/kg THC developed gradually over the course of daily treatment, and total urine output
following 10.0 mg/kg THC on day 7 was identical to urine output following saline treatment.
Changes in urine output following daily treatment with 10.0 mg/kg THC for 7 days correlated
well with changes in weight loss in mice over the 6 hr test period and changes in water intake
over 24 hr following testing (shown in Figure 19). This suggests that increases in urine output is
accompanied by corresponding weight loss and an increase in water intake, and as tolerance
develops to the diuretic effects of THC, effects on weight loss and water intake also dissipate.
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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1 3 5 7 9
0
1 0
2 0
3 0
4 0 V e h ic le
1 0 .0 m g /k g T H C
D a y s
Urin
e (
g/k
g)
1 3 5 7 9
0
1 0
2 0
3 0
4 0
D a y s
Wa
ter i
nta
ke
/ca
ge
(g
)
1 3 5 7 9
0
1
2
3
D a y s
We
igh
t lo
ss
(g
)
Figure 19: Effects of 10 mg/kg THC or vehicle injections determined over time (days), on urine
output (top), water intake over 24hr (middle) and weight loss over 6 hr (bottom) (n =6).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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Tolerance that developed to the increases in urine output after 7 daily injections of 10.0
mg/kg THC extended to other doses of THC as the entire THC dose-response curve was shifted
to the right after 7 days of 10.0 mg/kg THC administration as compared to vehicle treatment
(Figure 20). The ED50 value for the diuresis produced by THC in mice that received 10.0 mg/kg
THC for 7 days was 25.8 mg/kg as compared to an ED50 of 3.8 mg/kg in vehicle treated mice,
corresponding to an approximate 7-fold increase in ED50 for the ascending limb of THC dose
response curve. Tolerance also developed to the decrease in diuresis produced at higher dose
(30-100 mg/kg) of THC; doses higher than 100.0 mg/kg were not tested due to solubility issues,
and so the magnitude of shift in the descending limb could not be determined.
The reversibility of tolerance to the diuretic effects of THC was evaluated by
determination of THC dose response curve 14 days after stopping daily THC injections.
Increases in urine output after 10.0 mg/kg THC were intermediate to those obtained on days 1
and 8 and were not statistically different from either, suggesting partial recovery of the diuretic
effects of THC. In contrast, recovery to the decrease in urine output produced by 100.0 mg/kg
THC was complete after the 14 day recovery period (Figure 20).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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0
10
20
30
40
7 day 10 mg/kg THC
7 day vehicle
1.0 3.0 10.0 30.0 100.0
14 day post 7 day 10 mg/kg THC
THC (mg/kg)
Uri
ne (
g/k
g)
Figure 20: Urine output measured in mice treated with vehicle or 10.0 mg/kg once a day for 7
days and tested on day 8 with THC. THC dose response curve following 14 days after last
injection of THC on day 7 (n = 6).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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4.4.2 Tolerance to antinociception: Results describe in Chapter 3 indicate that
10.0mg/kg approximates an ED50 dose in increasing antinociception. The effects of daily 10.0
mg/kg THC on the development of tolerance to cannabinoid antinociceptive effects was
evaluated as a comparison to the tolerance that was observed to the diuretic effects of this dose.
Tolerance to the antinociceptive effects of 10.0 mg/kg THC developed rapidly, within 3 days,
and persisted for the duration of the daily dosing regimen (Figure 21).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
94
1 3 5 7 9
0
2 0
4 0
6 0
8 0
1 0 0
1 0 .0 m g /k g T H C
D a y s
% M
PE
Figure 21: Antinociception measured every other day 1 hr post 10.0 mg/kg THC (n = 6).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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Similar to studies that were performed with diuresis, dose response curves for THC were
determined before and after administration of 10.0 mg/kg THC once a day for 7 days. The THC
dose response curve was shifted to the right (Figure 22) after 7 day exposure to THC, with the
ED50 changing from 9.5 mg/kg to 87.1 mg/kg, corresponding to an approximate 9-fold increase
in ED50 values. Similar to diuresis studies, the mice that received 10.0 mg/kg THC for 7 days
were allowed to recover for 14 days and then the antinociceptive effects of THC were re-
determined. The dose response curve for THC after the recovery period was slightly to the left
of THC dose response curve obtained immediately after the 7 day THC treatment period, as seen
in Figure 22. The ED50 value for THC 14 days after stopping the daily injections was 60.5
mg/kg, indicating incomplete recovery of the antinociceptive effects of THC.
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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0
20
40
60
80
100
7 day vehicle
7 day 10 mg/kg THC
14 day post 7 day 10 mg/kg THC
1.0 3.0 10.0 30.0 100.0
THC (mg/kg)
% M
PE
Figure 22: Antinociception after cumulative THC injections, expressed as %MPE, in mice
treated with vehicle or 10.0 mg/kg once a day for 7 days and tested on day 8 with THC, and THC
testing 14 days after last THC injection on day 7 (n = 6).
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4.4.3 Changes in CB1 receptor levels: Changes in CB1 receptor levels were determined
in mice that received 7-day treatment with 10.0 mg/kg THC. The Bmax for CB1 receptors in the
group of mice treated with vehicle was 170 ± 30 pmol/mg (n=6). Preliminary studies also
determined effects of single injections of 1.0-30.0 mg/kg THC on CB1 receptor binding at 24 hr
after injection and found no significant changes in CB1 receptor binding, with Bmax values that
ranged from 116 to 245 pmol/mg (n=2-3). The Bmax value for mice that received THC for 7 days
was 75 ± 9 pmol/mg (n = 6) and were significantly lower than Bmax values obtained from vehicle
treated mice (p = 0.013). As a positive control, another group of mice was treated with the CB1
full agonist, AM2389, at a dose 0.1 mg/kg/day for 7 days; this dose is adequate to see signs of
rimonabant-precipitated withdrawal symptoms in mice (unpublished data). Daily injection with
0.1 mg/kg AM2389 for 7 days resulted in a Bmax value for CB1 receptors of 34 ± 5 pmol/mg (n =
6) and was significantly different from vehicle treated mice (p = 0.001).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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0 30 60 90 120 1500.000
0.005
0.010 7 day vehicle
7 day 0.1 mg/kg AM2389
7 day 10.0 mg/kg THC
Bound [pmol/mg]
Bo
un
d/F
ree
0
500
1000
1500
2000
-12 -10 -8 -6 -40
AM281 [M]
CP
M (
tota
l b
ind
ing
)
Figure 23: Binding data for CB1 receptors, (bottom) total binding in the presence of increasing
concentrations of cold AM281, dotted line represents non-specific binding. Top, Scatchard plot
of the same data for determining Bmax by extrapolation (n = 6).
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4.5 Discussion:
Cannabinoids produce diuresis in mice by activation of the CB1 receptors. Tolerance to many
cannabinoid CB1-mediated effects, such as antinociception, hypothermia, rate of operant
responding and hypolocomotion have been reported (Wiley et al., 2005; Wiley et al., 2007;
Nguyen et al., 2012; Desai et al., 2013). These studies sought to determine if the diuretic effects
of cannabinoids are likewise subject to tolerance. The dose of 10 mg/kg THC is
pharmacologically active and represents the peak dose for increasing diuresis (shown in chapter
2), however it is relatively low dose based on effects in other murine assays, for example, it is
approximately the ED50 dose for antinociceptive effects. Often 20 mg/kg/day THC, or even
higher doses, administered for 5-7 days are used to study cannabinoid physical dependence in
mice and are considered necessary to produce tolerance to the pharmacological effects of THC in
mice (Breivogel et al., 1999; Sim-Selley et al., 2006). Here, a dose of 10mg/kg/day for 7 days
was selected to study tolerance, primarily based on unpublished work from our lab and evidence
from the literature that indicate signs of precipitated withdrawal are obtained following this
dosing regimen (Cook et al., 1998). Tolerance developed to both the diuretic and antinociceptive
effects produced by 10 mg/kg THC, with diuretic tolerance perhaps emerging more gradually
than tolerance to the antinociceptive effects of THC. Along with tolerance to the diuretic
effects, the amount of water intake also proportionally decreased over 24 hr following diuresis
testing and was accompanied by proportional decreases in loss of body weight over the 6 hr
testing period. This suggests that loss in body weight was primarily due to fluid loss, which was
recovered by fluid intake after the test session, although this was not directly assessed.
Complete dose response curve determinations with THC in mice after 7 days of 10 mg/kg
THC or vehicle demonstrated that tolerance developed to both the ascending and descending
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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limb of the diuresis dose response curves. The shift in the ascending limb of the diuresis dose
response curve in THC-treated mice after 7 days of 10 mg/kg/day THC treatment was
approximately 7-fold and was similar in magnitude to the shift in the dose response curve
observed for antinociception (~9-fold). This suggests similar CB1 receptors might be involved
in mediating the antinociceptive and diuretic effects of THC in mice and further supports the
findings from chapter 2 that cannabinoid agonists produce increases in diuresis by actions at the
CB1 receptors in the CNS.
To investigate if the development of tolerance to the diuretic and antinociceptive effects
of cannabinoids was accompanied by changes in CB1 receptor binding parameters in the brain,
radioligand binding was performed on mouse cerebellum. Mice that were treated acutely with 1-
30 mg/kg THC showed no significant changes in CB1 receptor numbers in the mouse cerebellum
as compared to vehicle treated animals. However, mice that received 10 mg/kg/day THC
treatment for 7 days showed a statistically significant reduction in CB1 receptors when compared
to vehicle treated animals. As the effects of only a single daily dose (10mg/kg) of THC were
evaluated, one can only speculate that the Bmax for the CB1 receptors would decrease
proportionally to an increase in dose. Others have also reported that CB1 receptors are down
regulated significantly in the cerebellum following 6.5 day of 10 mg/kg THC twice daily dosing
(Nguyen et al., 2012).
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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The use of cerebellum tissue for determining CB1 receptor down regulation may not be
ideal for understanding tolerance to cannabinoid-mediated diuresis; it is more likely that CB1
receptors in the hypothalamus are involved in endocrine functions responsible for maintaining
fluid homeostasis (Goodman et al., 2006). However, binding studies in mouse hypothalamus
using frozen brain tissues are difficult; hence the cerebellum was used as a proxy to indicate
overall changes in brain CB1 receptors. One study comparing effects of sub-chronic THC
dosing showed that although decreases in CB1 receptors in the hypothalamus were observed,
they were not as significant compared to the decreases produced in the cerebellum (Nguyen et
al., 2012). The regional differences in receptor downregulation following sub-chronic
cannabinoid treatment could implicate possible role of CB1 receptors in specific regions of the
brain in producing tolerance to the pharmacological effects of cannabinoids.
After demonstrating that tolerance developed to the diuretic and antinociceptive effects of
THC after 7 day 10mg/kg/day THC administration, and that this tolerance was accompanied by
changes in CB1 receptors in the cerebellum, studies next tried to identify whether this tolerance
was reversible after cessation of daily drug administration. 14 days after the last injection of
THC, dose response curves were re-determined for diuresis and antinociception and,
surprisingly, complete recovery was not observed for the ascending limb of cannabinoid diuresis
or for antinociceptive effects, suggesting the same (possibly CNS) CB1 receptors are involved in
producing the two effects. However, the descending limb of cannabinoid diuresis recovered
completely at day 14 indicative of the involvement of a distinct population of CB1 receptors
(possibly peripheral) in producing these effects. The above hypothesis supports the findings
from chapter 2 that central CB1 receptor activation is associated with increasing diuresis while
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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peripheral CB1 receptors are involved in producing the decreases in diuresis produced by
cannabinoid agonists in mice.
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E. Conclusions:
This thesis research establishes diuresis as a robust cannabinoid-mediated effect in mice
and, further, identifies the receptor mechanisms that underlie these effects. Initial parametric
work involved developing and validating a simple, cost effective method of measuring urine
output in individual mice. Once developed, these procedures were used to compare cannabinoid
diuresis with diuresis produced by other drugs and, as well, to compare cannabinoid diuresis with
another well characterized cannabinoid-mediated effect, antinociception. The major findings of
this work, that THC and other synthetic cannabinergic compounds produce diuresis in mice,
extend previous reports of the diuretic effects of cannabinoids in rats and humans (Ames, 1958;
Sofia et al., 1977; Paronis et al., 2013). The order of potency for the structurally distinct
cannabinoid agonists - THC, WIN55,212-2, AM7418 and AM4054 – in producing diuresis was
similar to the order of potency for antinociception, notably, however, peak diuretic effects
occurred at doses lower than peak antinociceptive effects. The finding that all cannabinoids
were more potent in terms of producing diuresis than they were antinociception suggests that
diuresis may represent a more sensitive and objective measure of cannabinoid actions in vivo
than other commonly used behavioral assays.
The cannabinoid agonists increased urine output in a manner qualitatively and
quantitatively more similar to that produced by the κ-opioid agonist U50,488 than the loop
diuretic, furosemide. Quantitatively, the four cannabinoids produced maximum urine outputs of
30-36 g/kg, equivalent to the outputs achieved with high doses of U50,488, and less than
amounts voided after furosemide. Qualitatively, the relatively small Na+ loss following THC
indicates weak naturetic effects that are more similar to the free water diuresis produced by U-
50,488 than the electrolyte loss that accompanies furosemide diuresis. However, unlike the κ-
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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opioid agonist and the loop diuretic, the cannabinoid agonists had biphasic dose-effect functions,
and doses above those that yielded 30-36 g/kg urine led to dose-dependent decreases in urine
output. Such biphasic functions were not noted in previous studies in rats and may represent a
distinct difference between species.
The involvement of specific cannabinoid receptors in modulating urine output was
investigated through pharmacological antagonism studies. To this end, receptor selective
antagonists rimonabant or AM630, and the peripherally constrained antagonist AM6545, were
used as pretreatment drugs (Rinaldi-Carmona et al., 1995; Ross et al., 1999; Tam et al., 2010).
The cannabinoid CB1 antagonist rimonabant had no intrinsic effects on diuresis yet did dose-
dependently antagonize both the ascending and descending limbs of the AM4054 dose response
curve. In contrast to rimonabant, the CB2 antagonist AM630 did not attenuate the effects of
either moderate or high doses of AM4054 or THC. Together, these results suggest that, as in
rats, cannabinoid agonists produce their diuretic effects in mice via actions at cannabinoid CB1
receptors with limited involvement of CB2 receptors. Moreover, since both limbs of the
AM4054 dose-response curve were antagonized by rimonabant, our data further indicate that
both the increases and subsequent decreases in the magnitude of diuresis are CB1-mediated.
This was further confirmed by comparing the potency ratios for rimonabant across
antinociception and diuresis, which revealed greater potency towards antagonizing increases in
diuresis and identical potency ratios for antagonizing antinociception and decreases in diuresis.
Repeated administration of THC for 7 days resulted in development of tolerance to the
diuretic as well as antinociceptive effects of THC. For diuresis, both the ascending and
descending limbs of the THC dose response curve were shifted to the right, yet the recovery
from tolerance was different for these two effects, suggesting that different sub-population of
Doctoral Dissertation, Northeastern University Investigator: Girish Rajmal Chopda
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CB1 receptor are responsible for the two limbs of cannabinoid diuresis dose response curve.
One hypothesis was that these effects occur by activation of CB1 receptors in two separate
compartments, i.e., those found either centrally or peripherally. The quantitative and qualitative
similarity between cannabinoid and κ-opioid diuresis suggested central mediation of the increase
in urine output, as U50,488 is known to produce its diuretic effects through central actions
(Kapusta and Obih, 1993; Kapusta and Obih, 1995). To test this hypothesis, the peripherally
constrained cannabinoid CB1 antagonist AM6545 (Cluny et al., 2010; Tam et al., 2010) was
injected prior to determination of a full AM4054 dose-effect function. A moderate dose of
AM6545 did not affect the ascending limb of the AM4054 function, while shifting the
descending limb of AM4054 diuresis to the right; a higher dose of AM6545 was able to shift
both limbs of the AM4054 dose effect function. Although AM6545 does not readily cross the
blood-brain barrier, higher doses will penetrate the CNS and have been associated with blockade
of central antinociceptive effects of THC in the warm water tail-withdrawal measurement.
Though limited, these data suggest that diuresis produced by lower doses of agonists are central
cannabinoid CB1 receptor effects, however, the decrease in the magnitude of diuresis produced
at higher doses of agonists likely involves both central and peripheral cannabinoid CB1
receptors. If this is correct, than the results of the tolerance studies suggest that perhaps the
peripheral cannabinoid receptors recovery more quickly during daily dosing regimens than do
the central CB1 receptors. In concordance with this, there was very little recovery of the
centrally-mediated antinociceptive effects of THC following daily dosing. Hence we can
conclude that cannabinoids increase diuresis and produce antinociception by actions at the
central CB1 receptors whereas they decrease diuresis possibly by actions at the peripheral CB1
receptors.
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Clinical studies have reported beneficial effects of smoked or aerosolized cannabis on
bladder dysfunction in patients with multiple sclerosis, primarily by decreasing urinary
frequency in these subjects following marijuana use (Consroe et al., 1997; Brady et al., 2004).
These reports contrast with the earlier clinical reports demonstrating increase in urine output
after cannabis administration (Ames, 1958). Our findings in mice demonstrate both dose related
increases and decreases in urine output, providing a platform for understanding the mixed effects
on urine output observed with marijuana in various clinical studies. As noted earlier in a study
with rats (Sofia et al., 1977), the diuresis induced by THC in mice also is weakly naturetic
compared to furosemide and further investigations in this area may yield a new, clinically
beneficial diuretic. In contrast, our data suggest that development of peripherally selective
cannabinoid CB1 agonists may be beneficial for patients suffering from bladder dysfunction.
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G. Appendix:
Completion of Investigator assessment quiz for working with research animals
User: Girish Chopda
Submitted: 10/08
Name: Investigator Assessment Quiz
Status: Completed
Score: 100 out of 100 points
Instructions: This test consists of 20 multiple choice and/or True/False questions. You must answer all
questions. You will be notified at the end of the test whether you passed (hopefully) or failed. 70% of the
questions must be answered correctly to pass. If you fail you must read the training module and take the
test again. If you pass, you will be given approval from the NU-IACUC and the DLAM to work with