Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats

2020 ◽  
Author(s):  
Tayfun Baser ◽  
Ercan Ozdemir ◽  
Ahmet Kemal Filiz ◽  
Ahmet Sevki Taskiran ◽  
Sinan Gursoy
Keyword(s):  
Analgesic Activity ◽  
Receptor Agonist ◽  
Morphine Tolerance ◽  
Peptide Hormone ◽  
Tail Flick ◽  
Analgesic Tolerance ◽  
Ghrelin Receptor ◽  
Analgesic Effects ◽  
Ghrelin Receptor Agonist ◽  
Ghrelin Receptor Antagonist

Ghrelin is a peptide hormone released from the gastric endocrine glands and shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not been elucidated yet. The purpose of the study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [D-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adults rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance a 3-day cumulative dose regimen was used in rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg/kg), [D-Lys3]-GHRP-6 (10 mg/kg), and morphine (5 mg/kg) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [D-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Besides, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.

The nitric oxide–cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine

2011 ◽  
Vol 89 (2) ◽  
pp. 89-95 ◽  
Author(s):  
Ercan Ozdemir ◽  
Ihsan Bagcivan ◽  
Nedim Durmus ◽  
Ahmet Altun ◽  
Sinan Gursoy
Keyword(s):  
Nitric Oxide ◽  
Analgesic Effect ◽  
Soluble Guanylate Cyclase ◽  
Morphine Tolerance ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Albino Rats ◽  
Tail Flick ◽  
Analgesic Effects ◽  
Cgmp Signaling

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180–210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), NG-nitro-l-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide–cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.

Integrated Approach to Early Detection of Cardiovascular Toxicity Induced by a Ghrelin Receptor Agonist

2015 ◽  
Vol 34 (2) ◽  
pp. 151-161 ◽  
Author(s):  
Alan H. Stokes ◽  
J. Greg Falls ◽  
Lawrence Yoon ◽  
Neal Cariello ◽  
Brenda Faiola ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Receptor Agonist ◽  
Troponin I ◽  
Troponin T ◽  
Heart Weight ◽  
Repeat Dose ◽  
End Points ◽  
Fatty Acid Binding ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.3, 1, 10, or 60 mg/kg/d, we dosed rats across a range of similar doses (0, 0.3, 60, or 150 mg/kg/d) for 7 days to determine whether CV toxicity could be detected in a shorter study. End points included light and electron microscopies of the heart; heart weight; serum concentrations of fatty acid-binding protein 3 (FABP3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and N-terminal proatrial natriuretic peptide (NT-proANP); and a targeted transcriptional assessment of heart tissue. Histologic evaluation revealed a minimal increase in the incidence and/or severity of cardiac necrosis in animals administered 150 mg/kg/d. Ultrastructurally, mitochondrial membrane whorls and mitochondrial degeneration were observed in rats given 60 or 150 mg/kg/d. The FABP3 was elevated in rats given 150 mg/kg/d. Cardiac transcriptomics revealed evidence of mitochondrial dysfunction coincident with histologic lesions in the heart, and along with the ultrastructural results support a mechanism of mitochondrial injury. There were no changes in cTnI, cTnT, NT-proANP, or heart weight. In summary, enhancing a study design with novel end points provides a more integrated evaluation in short-term repeat dose studies, potentially leading to earlier nonclinical detection of structural CV toxicity.

scholarly journals Population pharmacokinetics (PPK) of anamorelin (ANAM), an oral selective ghrelin receptor agonist

2018 ◽  
Vol 29 ◽  
pp. viii616-viii617 ◽  
Author(s):  
A. Bernareggi ◽  
S. Kaasa ◽  
M. Fallon ◽  
R.J.E. Skipworth ◽  
D. Currow
Keyword(s):  
Population Pharmacokinetics ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

scholarly journals Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers

2016 ◽  
Vol 28 (11) ◽  
pp. 1705-1713 ◽  
Author(s):  
A. D. Nelson ◽  
M. Camilleri ◽  
A. Acosta ◽  
I. Busciglio ◽  
S. Linker Nord ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Receptor Agonist ◽  
Motor Functions ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

Investigation of the effectiveness of a ghrelin receptor agonist to stimulate the defecation centre in spinal cord injured rats

2011 ◽  
Vol 163 (1-2) ◽  
pp. 58
Author(s):  
J.B. Furness ◽  
D.M. Ferens ◽  
M.D. Habgood ◽  
N.R. Saunders ◽  
D.J. Brown ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist ◽  
Spinal Cord Injured

Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice

Peptides ◽  
2014 ◽  
Vol 55 ◽  
pp. 103-109 ◽  
Author(s):  
Ping Zeng ◽  
Shu Li ◽  
Yue-hui Zheng ◽  
Fu-Yan Liu ◽  
Jing-lei Wang ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Antinociceptive Effects ◽  
Ghrelin Receptor Agonist
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