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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
DAMGO has served as the standard μ opioid receptor ligand since its introduction in 1981 (Kosterlitz and Paterson, 1981; Handa et al., 1981). DAMGO is an agonist with at least 100-fold greater affinity for μ relative to δ opioid receptors (James and Goldstein, 1984; Hawkins et al., 1989). The Ki value of DAMGO for κ opioid receptors has been measured as 2 to 3 μM using [3H]EKC or > 1 μM using [3H]PD 117302. DAMGO has reasonably high affinity for μ opioid receptors with estimates ranging from 0.73 nM (Hawkins et al., 1988) to 4.3 nM (James and Goldstein, 1984) for binding to brain homogenates and 1.4 nM for binding to rat brain tissue sections (Mansour et al., 1986). Assuming that the μ, δ, and κ receptors represent independent sites, it is possible to estimate their relative occupation by a given concentration of DAMGO using the mass action equation:
Appetite Control in C. elegans
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Kristen Davis, Mi Cheong Cheong, Ji Su Park, Young-Jai You
Many studies have shown that the opioid system modulates food intake; blocking the opioid receptor by naloxone, an opioid receptor blocker, decreases food intake. On the other hand, treating animals with an agonist of the opioid receptor increases food intake (Martin et al. 1963), and β-endorphin stimulates food intake when administrated directly into the ventromedial hypothalamus (Grandison and Guidotti 1977). Selective agonists for the μ receptor (DAMGO), the δ receptor (DADLE), and the κ receptor (U50448) also increase food intake (Tepperman and Hirst 1983, Gosnell et al. 1986, Jackson and Cooper 1986). In addition to the homeostatic regulation, opioids also regulate the hedonic food intake, by modulating the palatability of food. Naloxone suppresses intake of sucrose solution and blocks the preference for saccharin solution (Levine et al. 1982, Lynch and Burns 1990). An opioid agonist, DAMGO, increases saccharin intake (Zhang and Kelley 2002).
The Circuitry Mediating the Translation of Motivational Stimuli Into Adaptive Motor Responses
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Peter W. Kalivas, Lynn Churchill, Mark A. Klitenick
Alterations in enkephalin transmission are also produced by 6-OHDA lesions of the nucleus accumbens or chronic administration of DA antagonists. Both enkephalin protein and mRNA content is elevated, indicating an increase in synthesis and turnover of enkephalin.226–228 In addition to presynaptic alterations, the capacity of opioids microinjected into the nucleus accumbens to produce motor activity is dramatically augmented.110,111Figure 13 shows that the augmented locomotor activity is observed after inhibition of enkephalin metabolism by kelatorphan microinjection into the nucleus accumbens, indicating that endogenous enkephalin transmission can also elicit the enhanced postsynaptic response. When receptor subtype selective agonists are microinjected into the nucleus accumbens, the mu selective drug, DAMGO, demonstrates marked sensitization of motor activity in lesioned rats, while the delta selective agonist, DPDPE, does not.229 Surprisingly, unlike the increased behavioral response to D2 agonists in lesioned animals, the increased response to DAMGO is not associated with an upregulation in mu receptors.229 Likewise, no alteration in DAMGO-induced inhibition of adenylyl cyclase activity was measured in the nucleus accumbens of lesioned rats (unpublished observation). Not only is the increased postsynaptic responsiveness to mu opioids reflected in augmented locomotor activity, but rats treated with chronic DA antagonists are more sensitive to the reinforcing effects of systemic heroin.230 The upregulation in enkephalin transmission in lesioned rats appears to be a compensatory alteration to overcome the loss of DA transmission. Thus, while DA normally functions as a transmitter in the nucleus accumbens to modulate the transfer of information from the hippocampus and amygdala to the nucleus accumbens, in rats lacking DA innervation, enkephalin may serve this role. Thus, the influence of mu opioid receptor stimulation on both locomotion and reinforcing behaviors is enhanced. The increased importance of enkephalin transmission is supported by the fact that in sham-lesioned rats locomotor activity elicited by picrotoxin microinjection into the VP is only marginally attenuated by systemic naloxone administration.109,231 However, in rats sustaining accumbal DA lesions, naloxone abolishes the motor stimulation by picrotoxin in the VP. Furthermore, Figure 14 shows that a similar increased efficacy of opioid blockers is revealed by the microinjection of naltrexone methobromide into the nucleus accumbens. Thus, the role of accumbal enkephalin transmission in regulating motor output from the motive circuit is augmented in lesioned rats.
Sucrose drinking mimics effects of nucleus accumbens µ-opioid receptor stimulation on fat intake and brain c-Fos-expression
Published in Nutritional Neuroscience, 2022
L.L. Koekkoek, A. Masís-Vargas, T. Kool, L. Eggels, L.L. van der Gun, K. Lamuadni, M. Slomp, C. Diepenbroek, A. Kalsbeek, S.E. la Fleur
As it is known that stimulation of the NAC μ-opioid receptors, both by endogenous as well as synthetic opioids, can increase food intake [9–13, 25], one would expect that if sucrose drinking indeed causes the release of endogenous opioids in the NAC, this would trigger food intake as well. Indeed, we found increased consumption of fat throughout the five hours after vehicle infusion. Specifically, in the second half of those five hours, the other experimental groups showed minimal fat intake, indicating that sucrose drinking prolongs the period of fat consumption at the beginning of the dark period, compared to control groups. Thus, while intra-NAC DAMGO infusion causes a sharp increase in fat intake in the first two hours, sucrose drinking causes a steady increase in fat intake, resulting in comparable amounts of fat consumed after five hours. Strikingly, when DAMGO was infused after sucrose drinking, it did not increase fat intake during the first two hours (as seen in the fcHF W DAMGO group), but it also lowered fat intake in the two-five hour window after infusion compared to the fcHF S vehicle group. One possible explanation for this is that DAMGO is known to enhance the internalization of μ-opioid receptors [26], thereby possibly altering the effects that the sucrose drinking-induced release of endogenous opioids has on fat intake.