Translational Analytical Core – Publications

@article{pmid33997152,

title = {κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats},

author = {Renata C N Marchette and Adriana Gregory-Flores and Brendan J Tunstall and Erika R Carlson and Shelley N Jackson and Agnieszka Sulima and Kenner C Rice and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/33997152/},

doi = {10.1016/j.ynstr.2021.100325},

issn = {2352-2895},

year  = {2021},

date = {2021-05-01},

urldate = {2021-05-01},

journal = {Neurobiol Stress},

volume = {14},

pages = {100325},

abstract = {Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2-6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4-6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg  2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5'-guanidinonaltrindole (5'GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days  7 days), whereas 5'GNTI had more prolonged effects in females than in males (14 days  4 days). The behavioral effects of 5'GNTI coincided with higher 5'GNTI levels in the brain than in plasma when measured at 24 h, whereas 5'GNTI did not reverse hyperalgesia at 30 min posttreatment when 5'GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5'GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34590334,

title = {Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder},

author = {Olli Kärkkäinen and Mehdi Farokhnia and Anton Klåvus and Seppo Auriola and Marko Lehtonen and Sara L Deschaine and Daria Piacentino and Kelly M Abshire and Shelley N Jackson and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/34590334/},

doi = {10.1111/acer.14719},

issn = {1530-0277},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Alcohol Clin Exp Res},

volume = {45},

number = {11},

pages = {2207--2216},

abstract = {BACKGROUND: Ghrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD).



METHODS: We used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session.



RESULTS: In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value = 0.0003 and IV-AC q < 0.0001), corticosterone (IV-ASA q = 0.0202 and IV-AC q < 0.0001), and glycochenodeoxycholic acid (IV-ASA q = 0.0375 and IV-AC q = 0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458).



CONCLUSION: IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}