Separation of emetic and anorexic responses of exendin-4, a GLP-1 receptor agonist in Suncus murinus (house musk shrew)

Chan, Sze Wa; Lin, Ge; Yew, David T.; Yeung, Chi Kong; Rudd, John A.

doi:10.1016/j.neuropharm.2013.01.013

Cited by 23 publications

(34 citation statements)

References 32 publications

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“…In the follow up study comparing animals that readily vomited to motion, with those selectively bred to be insensitive, c-fos expression could still be observed in the animals that were less response following the 30 min stimulus (Ito et al, 2005). One of the major differences between our studies and those previously published, therefore, is the duration of the stimulus, and not the number of episodes (Chan et al, 2013, 2014). If this is indeed the case, it is possible that the pattern of c-fos expression seen following longer exposure times to motion does not exclusively relate to emetic mechanisms alone and may include motion-induced changes in blood flow, discomfort and stress or malaise and/or nausea (See Ito et al, 2003, 2005; Yates et al, 2014).…”

Section: Discussioncontrasting

confidence: 72%

“…Our previous studies using Suncus murinus have shown that stimuli inducing 6–20 episodes of emesis (average from all studies ~10 episodes) are associated with significant increases of c-fos expression in the brainstem (NTS, AP), hypothalamus and amygdala (Chan et al, 2013, 2014). However, our motion stimulus, which produced ~10 episodes over 10 min, did not.…”

Section: Discussionmentioning

confidence: 98%

“…The methodology for c-fos immunohistochemistry followed that previously used in studies of pathways implicated in emesis in Suncus murinus (Chan et al, 2013, 2014). In brief, frozen tissues were sectioned at 40 μm in the coronal plane using a freezing microtome and incubated at room temperature for 1 h in 0.03% H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The number of c-fos immunoreactive cells was counted manually using a Zeiss Axioskop 2 plus microscope (Carl Zeiss Inc. Thornwood, USA) equipped with a Zeiss Axiocam 2 camera. To quantify expression in brainstem and hypothalamic nuclei, three representative sections were selected in accordance with the stereotaxic atlas constructed from our previous studies (Chan et al, 2013, 2014). Specifically, the anterior-posterior coordinates (measured from lambda) of the sections in which c-Fos were counted: +5.32, +5.44, and +5.66 for the ventral medial nucleus of hypothalamus (VMH), dorsal medial nucleus of hypothalamus (DMH), peduncular part of lateral hypothalamus (PLH), and arcuate nucleus (Arc); +5.92, +6.04, and +6.28 for paraventricular nucleus of hypothalamus (PVH); +0.50, +0.62, and 0.74 for medial vestibular nucleus (MVe); −0.26, −0.14, and −0.02 for the area postrema (AP) and nucleus tractus solitarius (NTS).…”

Section: Methodsmentioning

confidence: 99%

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Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Dieser

et al. 2017

Front. Physiol.

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Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Dieser

et al. 2017

Front. Physiol.

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“…For the GLP-1 system as a whole, our opinion is that a critical mass of studies have been conducted (some reviewed here) with congruent findings to suggest that GLP-1R signaling affects food reward and drug taking. We point out however, that unequivocal data has been reported showing that the GLP-1 system is also involved in stress, visceral malaise, nausea and emetic events[7,22,25,42-45]. We also believe that current GLP-1-based pharmacotherapies at select doses can be a useful tool to treat obesity, eating disorders, and drug/alcohol addiction; however, further basic and clinical trials are still needed to evaluate these hypotheses.…”

Section: Does Glp-1 Really Affect Reward?mentioning

confidence: 87%

GLP-1 influences food and drug reward

Hayes¹,

Schmidt

2016

Current Opinion in Behavioral Sciences

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Natural rewards, including food, water, sleep and social interactions, are required to sustain life. The neural substrates that regulate the reinforcing effects of these behaviors are also the same neurobiological mechanisms mediating mood, motivation and the rewarding effects of pharmacological stimuli. That the neuropeptide glucagon-like peptide-1 (GLP-1) is under investigation for both the homeostatic and hedonic controls of feeding is not surprising or novel. However, if the neural substrates that underline food reward are shared with other reward-related behaviors generally, then future research should investigate and embrace the likelihood that endogenous and exogenous GLP-1 receptor activation may influence multiple reward-related behaviors. Indeed, studies of the neurobiological mechanisms underlying motivated feeding behavior have informed much of the basic research investigating neural substrates of drug addiction. An emerging literature demonstrates a role for the GLP-1 system in modulating maladaptive reward behaviors, including drug and alcohol consumption. Thus, if GLP-1-based pharmacotherapies are to be used to treat drug addiction and other diseases associated with maladaptive reward behaviors (e.g. obesity and eating disorders), the neuroscience field must conduct systematic, mechanistic neuropharmacological and behavioral studies of each GLP-1 receptor-expressing nucleus within the brain. It is possible that behavioral selectivity may result from these studies, which could inform future approaches to targeting GLP-1R signaling in discrete brain nuclei to treat motivated behaviors. Equally as likely, non-selective effects on natural reward and maladaptive reward behaviors may be observed for GLP-1-based pharmacotherapies. In this case, a better understanding of the effects of increased central GLP-1R activation on motivated behaviors will aid in clinical approaches toward treating aberrant feeding behaviors and/or drug dependence.

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Behavioural profile of exendin-4/naltrexone dose combinations in male rats during tests of palatable food consumption

Wright

Rodgers

2014

Psychopharmacology

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Similarities between the behavioural signature of exendin-4 and that previously reported for the emetic agent lithium chloride would suggest that exendin-4 anorexia is related to the aversive effects of the peptide. Furthermore, as low-dose combinations of the peptide with naltrexone failed to produce an additive/synergistic anorectic effect, this particular co-treatment strategy would not appear to have therapeutic significance.

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Separation of emetic and anorexic responses of exendin-4, a GLP-1 receptor agonist in Suncus murinus (house musk shrew)

Cited by 23 publications

References 32 publications

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew)

GLP-1 influences food and drug reward

Behavioural profile of exendin-4/naltrexone dose combinations in male rats during tests of palatable food consumption

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