Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and ...anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address.
Background and Purpose
To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5‐HT1A receptor activation in animal models.
Experimental Approach
We ...investigated the effect of CBDA on (i) lithium chloride (LiCl)‐induced conditioned gaping to a flavour (nausea‐induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion‐, LiCl‐ or cisplatin‐induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5‐HT1A receptor activation by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and mouse whole brain CB1 receptor activation by CP55940, using 35SGTPγS‐binding assays.
Key Results
In shrews, CBDA (0.1 and/or 0.5 mg·kg−1 i.p.) reduced toxin‐ and motion‐induced vomiting, and increased the onset latency of the first motion‐induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg−1 i.p.) suppressed LiCl‐ and context‐induced conditioned gaping, effects that were blocked by the 5‐HT1A receptor antagonist, WAY100635 (0.1 mg·kg−1 i.p.), and, at 0.01 mg·kg−1 i.p., enhanced saccharin palatability. CBDA‐induced suppression of LiCl‐induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg−1 i.p.). In vitro, CBDA (0.1–100 nM) increased the Emax of 8‐OH‐DPAT.
Conclusions and Implications
Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5‐HT1A receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
Recent studies have shown that the antidepressant fluoxetine induces anti-tumour activity in cancer cell lines such as colon, neuroblastoma, breast and ovarian carcinoma cells (Krishnan et al., 2008; ...Stepulak et al., 2008; Chung et al., 2009).
Background and Purpose
To evaluate the ability of cannabidiolic acid (
CBDA
) to reduce nausea and vomiting and enhance 5‐
HT
1A
receptor activation in animal models.
Experimental Approach
We ...investigated the effect of
CBDA
on (i) lithium chloride (
LiCl
)‐induced conditioned gaping to a flavour (nausea‐induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion‐,
LiCl
‐ or cisplatin‐induced vomiting in house musk shrews (
S
uncus murinus
); and (iv) rat brainstem 5‐
HT
1A
receptor activation by 8‐hydroxy‐2‐(di‐
n
‐propylamino)tetralin (8‐
OH‐DPAT
) and mouse whole brain
CB
1
receptor activation by
CP
55940, using
35
S
GTP
γ
S
‐binding assays.
Key Results
In shrews,
CBDA
(0.1 and/or 0.5 mg·kg
−1
i.p.) reduced toxin‐ and motion‐induced vomiting, and increased the onset latency of the first motion‐induced emetic episode. In rats,
CBDA
(0.01 and 0.1 mg·kg
−1
i.p.) suppressed
LiCl
‐ and context‐induced conditioned gaping, effects that were blocked by the 5‐
HT
1A
receptor antagonist,
WAY
100635 (0.1 mg·kg
−1
i.p.), and, at 0.01 mg·kg
−1
i.p., enhanced saccharin palatability. C
BDA
‐induced suppression of
LiCl
‐induced conditioned gaping was unaffected by the
CB
1
receptor antagonist,
SR141716A
(1 mg·kg
−1
i.p.).
In vitro
,
CBDA
(0.1–100
nM
) increased the
E
max
of 8‐
OH‐DPAT
.
Conclusions and Implications
Compared with cannabidiol,
CBDA
displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5‐
HT
1A
receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently,
CBDA
shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
In the present study, we investigated the effect of 5-hydroxytryptamine (5-HT) and 5-HT receptor agonists and antagonists on motion sickness in
Suncus murinus, and the possibility that the emetic ...stimulus of 5-HT can alter the sensitivity of the animals to the different emetic stimulus of motion sickness. 5-HT (1.0, 2.0, 4.0 and 8.0 mg/kg ip) induced emesis and that was antagonised by methysergide (1.0 mg/kg ip), the 5-HT
4 receptor antagonist sulphamate1-2-(methylsulphonyl)aminoethyl-4-piperidinylmethyl-5-fluoro-2-methoxy-1
H-indole-3-carboxylate (GR125487D; 1.0 mg/kg ip) and granisetron (0.5 mg/kg ip). Pretreatment with 5-HT caused a dose-related attenuation of the emetic response induced by a subsequent motion stimulus, which was not significantly modified by methysergide, granisetron or GR125487D pretreatment. (+)-1-(2,5-Dimethoxy-4-iodophenyl)-2-amino-propane (DOI; 0.5 and 1.0 mg/kg ip), 8-hydroxy-2(di-
n-propylamino)tetralin (8-OH-DPAT; 0.1 mg/kg ip) but not methysergide, GR125487D or granisetron, attenuated motion-induced emesis, and that was not affected by pretreatment with ketanserin (2.0 mg/kg, ip) or
N-{2-4-(2-methoxyphenyl)-1-piperazinylethyl}-
N-(2-pyridinyl)cyclohexanecarboxamide trihydrocholoride (WAY-100635; 1.0 mg/kg ip), respectively. Indeed, ketanserin alone (0.1, 0.3, 1.0 and 2.0 mg/kg ip) attenuated motion sickness. These data indicate that 5-HT
1/2, 5-HT
3 and 5-HT
4 receptors are involved in the induction of 5-HT-induced emesis. However, agonist action at the 5-HT
1A/7 and 5-HT
2 receptors, and antagonist action at the 5-HT
2A receptors can attenuate motion sickness in
S. murinus.
The aim of the present study was to investigate the effect of different frequency and amplitude of horizontal movements to induce motion sickness and to identify gender differences and adaptation to ...motion stimulus in adult
Suncus murinus. Each animal was subjected to a horizontal motion stimulus of 3, 7, 13, or 40 mm amplitude at a frequency of 0.5, 1, 2, or 3 Hz. The number of vomiting episodes and the latency of onset were recorded over a 10-min period. For the study of adaptation, different groups of males were exposed to repeated motion sickness (using 0.5 or 1 Hz frequency and the amplitude of 40 mm) either every 2 days for a period of 30 days, or once every week for a period of 28 days. In all animals the number of emetic episodes obtained at 1 and 2 Hz were significantly higher by 40–80% than those at 0.5 and 3 Hz using either 13 or 40 mm amplitude of movements; this was followed by shorter latency of emesis. Age-matched females were shown to be more responsive to the emetic stimuli than males as the number of emetic episodes at 1, 2, and 3 Hz (amplitude of 40 mm) were significantly higher by 33%, 42%, and 75%, respectively, than in males; this also was followed by a shorter latency of emetic response. In the study of adaptation, when used once every 2 days, by the second challenge (at 0.5 Hz) the number of emetic episodes was reduced by 62%, and to subsequent challenges emesis was absent or greatly reduced. Also, a reduction in responsiveness was observed at 1 Hz, which attained a maximum effect by the third challenge. The present results indicated that
Suncus murinus is sensitive to horizontal motion stimulus, the emetic episodes were significantly greater at 1 and 2 Hz than at either a lower or higher frequency, a repeated challenge once every 2 days but not weekly reduced the number of emetic episodes, and in all experiments, age-matched female animals were more responsive than males to motion stimulus and in some experiments this achieved significance.
The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in
Suncus murinus. Different groups of animals were treated ...intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of 1 Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, ip) or morphine (0.1 mg/kg, ip) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, ip) revealed an emetic response to morphine (
P<.001) (1.0 mg/kg, ip) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in
S. murinus.
The effects of 5‐HT and 5‐HT agonists to induce contraction and the 5‐HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus ...murinus.
The contraction curves to 5‐HT (3 nM–30 μM) were shifted to the right by methysergide (1 μM) and ritanserin (0.1 μM), without affecting the maximum response.
In the central and terminal segments (but not the proximal segments) ondansetron (1 μM) and atropine (1 μM) significantly attenuated the contractions to higher concentrations of 5‐HT. The selective 5‐HT4 receptor antagonist SB204070 (1 nM), failed to modify 5‐HT induced contractions in any segment examined.
5‐carboxamidotryptamine, α‐methyl‐5‐HT and 5‐methoxytryptamine (0.003–3.0 μM) induced contractions but unlike 5‐HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2‐methyl‐5‐HT (0.03–1.0 μM) was ten times less potent than 5‐HT to induce contraction but achieved the same maximum response.
The contractions induced by the lower concentrations of 2‐methyl‐5‐HT (0.03–1.0 μM) in all segments were markedly reduced or abolished by methysergide (1.0 μM); the response to the higher concentrations of 2‐methyl‐5‐HT (3–30.0 μM) were markedly reduced by atropine (1.0 μM) and ondansetron (1.0 μM).
In all segments examined, tetrodotoxin (1 μM) significantly reduced the 5‐HT‐induced contraction.
It is concluded that the 5‐HT‐induced contraction was mediated via 5‐HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5‐HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions.
British Journal of Pharmacology (1999) 127, 1867–1875; doi:10.1038/sj.bjp.0702729
The involvement of 5-HT2 receptor subtypes in mediating a contraction response in the isolated intestine of Suncus murinus was investigated using DOI ...((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane, a 5-HT2 receptor agonist) which produced a bell-shaped concentration response curve that was significantly (p < 0.05) reduced by methysergide (a 5-HT1/2 receptor antagonist, 1 microM) but not ketanserin (a 5-HT2A receptor antagonist, 1 microM), yohimbine (a 5-HT2B receptor antagonist, 1 microM) or a combination of ondansetron (a 5-HT3 receptor antagonist, 1 microM) plus SB204070 (8-amino-7-chloro(N-butyl-4-piperidyl) methylbenzo-1,4-dioxan-5-carboxylate hydrochloride, a 5-HT4 receptor antagonist, 1 nM). The contraction response to the lower concentrations of DOI (10 nM-0.3 microM) was reduced in the presence of SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo2 ,3-findole, a 5-HT2B/2C receptor antagonist, 1 microM), whilst conversely, the reducing response to the higher concentrations of DOI (1-30 microM) was prevented. A repeated challenge with 3 microM DOI produced a smaller response (desensitisation) and also reduced the response to 5-HT (5-hydroxytryptamine, 0.3 microM) that was inhibited by SB206553 (1 microM). Data indicate that 5-HT2C receptors are likely candidates to mediate the contractile response to DOI and demonstrate desensitisation to repeated challenges.
PDF
