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CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
The most selective radioligand presently available for the δ opioid receptor is [3H]DPDPE (James and Goldstein, 1984; Mansour et al., 1986). Kd values measured for [3H]DPDPE range from 1.1 (Akiyama et al., 1985) to 2.5 nM (Cotton et al., 1985). DPDPE inhibits [3H]CTOP binding at two sites, with Ki values of 254 and 9461 nM. Since neither value approaches the affinity of DPDPE for the δ opioid receptor, it is thought that the two sites represent different affinity states of the μ opioid receptor similar to those seen for pure μ opioid receptor binding with membranes prepared from 7315c pituitary tumor cells by Werling et al. (1988). The problem of ligand binding to multiple affinity states will be described later. For now, it is safe to assume that DPDPE has at least 100-fold greater selectivity for δ over μ opioid receptors. DPDPE has negligible binding affinity for κ opioid receptors labeled with [3H]PD 117,302 as the Ki, value is estimated to be over 10 μM (Clark et al., 1988). Using the average of the two DPDPE Kd values given above (1.8 nM), a 200 nM concentration of DPDPE would occupy 99, 44, and 0.2% of the populations of δ, μ, and κ opioid receptors, respectively.
Chronic opioid use modulates human enteric microbiota and intestinal barrier integrity
Published in Gut Microbes, 2021
Angélica Cruz-Lebrón, Ramona Johnson, Claire Mazahery, Zach Troyer, Samira Joussef-Piña, Miguel E. Quiñones-Mateu, Christopher M Strauch, Stanley L. Hazen, Alan D. Levine
Due to the decreased levels of Akkermansia muciniphila in methadone-treated individuals, we also explored the direct effects of methadone on barrier integrity. The monolayer was exposed to 1, 10, or 100 µM methadone at the basolateral surface – the equivalent of supplying methadone through the blood stream. In a dose dependent manner (Supplemental Figure S4) 100 µM methadone increased the strength of the intestinal barrier at 24, 48, and 72 h (p < .0001) (Figure 6a). In addition to methadone, we explored the effect of other exogenous opioids that selectively target the µ-OR on barrier integrity. Neither morphine nor [D-Ala,2 N-Me-Phe,4 Gly5-ol]-Enkephalin acetate salt (DAMGO) modulated barrier integrity (data not shown). Similarly, the κ-OR selective agonist BRL52537 hydrochloride and the δ-OR selective agonist [D-Pen 2,5] Enkephalin (DPDPE) did not regulate transepithelial resistance. The distinct kinetics of A. muciniphila spent media (Figure 5b) and methadone (Figure 6a) suggest different molecular mechanisms. Nonetheless, we explored if the combined effects of A. muciniphila spent media and methadone on the barrier might be additive or cooperative (Figure 6b). The combination treatment increased epithelial barrier integrity at 3 (p = .0004), 6 (p < .0001), 24 (p < .0001), 48 (p = .004), and 72 (p = .004) h, suggesting that the components of A. muciniphila spent media and methadone modulate intestinal barrier integrity independently with different kinetics.