THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors

Background and Purpose Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self‐medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β‐arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake. Experimental Approach We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil‐amide opioids for their ability to interact with G proteins and β‐arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties. Key Results Kratom alkaloids were strongly G protein‐biased at all three opioid receptors and reduced alcohol intake, but kratom and 7‐hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil‐amide opioid MP102—a G protein‐biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein‐biased μ opioid agonist TRV130 did not. Conclusion and Implications Our results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid‐selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.

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confidence: 99%

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

Gutridge

Robins

Cassell

et al. 2020

“…Nomenclature of targets and ligandsKey protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHAR-MACOLOGY(Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20: GPCRs, Section 104 Opioid Receptors(Alexander et al, 2019).4 | RESULTS4.1 | Relative contribution of central and peripheral MOP and DOP populations to the modulation of neuropathic painMOP showed different modulation of mechanical and heat nociceptive behaviour. CMV-MOP, Nav1.8-MOP and DLX5/6-MOP mice showed normal nociceptive thresholds in naïve and shamoperated conditions(Figure 1a,b).…”

mentioning

confidence: 99%

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

Martínez-Navarro

Cabañero

Wawrzczak-Bargieła

et al. 2020

Background and Purpose Mu and delta opioid receptors(MOP, DOP) contribution to the manifestations of pathological pain is not understood. We used genetic approaches to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations. Experimental Approach We generated conditional knockout mice with MOP or DOP deletion in sensoryNav1.8‐positive neurons (Nav1.8), in GABAergic forebrain neurons (DLX5/6) orconstitutively (CMV). Mutant mice and wild‐type littermates were subjected topartial sciatic nerve ligation (PSNL) or sham surgery and their nociception wascompared. Anxiety‐, depressivelike behaviour and cognitive performance were also measured. Opioid receptor mRNA expression, microgliosis and astrocytosis were assessed in the dorsalroot ganglia (DRG) and/or the spinal cord (SC). Key Results Constitutive CMV‐MOP knockouts after PSNL displayed reduced mechanical allodynia and enhanced heat hyperalgesia. This phenotype was accompanied by increased DOP expression in DRG and SC, and reduced microgliosis and astrocytosis in deep dorsal horn laminae. Conditional MOP knockouts and control mice developed similar hypersensitivity after PSNL, except for anenhanced heat hyperalgesia by DLX5/6‐MOP male mice. Neuropathic pain‐induced anxiety was aggravated in CMV‐MOP and DLX5/6‐MOP knockouts. Nerve‐injured CMV‐DOP mice showed increased mechanical allodynia, whereas Nav1.8‐DOP and DLX5/8‐DOP mice had partial nociceptive enhancement. CMV‐DOP and DLX5/6‐DOP mutants showed increased depressive‐like behaviour after PSNL. Conclusions and Implications MOP activity after nerve injury increased anxiety‐like responses involving forebrain GABAergic neurons and enhanced mechanical pain sensitivity along with repression of DOP expression and spinal cord gliosis. In contrast, DOP shows a protective function limiting nociceptive and affective manifestations of neuropathic pain.

“…Nomenclature of targets and ligandKey protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY(Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20(Alexander et al, 2019).…”

mentioning

confidence: 99%

The brain‐penetrating, orally bioavailable, ghrelin receptor agonist HM01 ameliorates motion‐induced emesis in Suncus murinus (house musk shrew)

Ngan

et al. 2020

Background and Purpose HM01, a novel, orally bioavailable, brain‐penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain‐penetrating ghrelin receptor agonist, HM02. Experimental Approach The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c‐Fos expression in brain sections was assessed. Key Results HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion‐induced emesis by 67.6%. Motion increased c‐Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c‐Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c‐Fos in the PVH. Both compounds antagonized the motion‐induced increases in c‐Fos expression in the MVe. Conclusions and Implications HM01 is more effective than HM02 in preventing motion‐induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.