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Transmitter Actions and Interactions on Pallidal Neuronal function
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Additional pallidal transmitter systems also may modulate a DA-activated striatopallidal system. Unilateral injections of 6-hydroxydopamine (6OHDA) into the medial forebrain bundle destroy the ascending dopaminergic projection in one hemisphere and allow for ipsilateral circling behaviors to be expressed with systemic treatments of apomorphine. This circling is attenuated with intra-GP microinjections of the κ opioid agonist, ethylketazocine (and not by morphine, DADL, levorphanol, or β-endorphin).152 However, intra-GP morphine (but not ethylketazocine) prevents the hyperactivity normally observed with activation of DA receptors restricted to the nucleus accumbens in unlesioned rats.58 These observations reveal that DA and opioids collectively mediate specific behaviors that may be under the control of particular arrangements of receptor subtypes. Another pallidal transmitter that can modify DA-induced motor function is glutamate, for amphetamine microinjections into the nucleus accumbens increase ambulations that are attenuated by VP treatments with glutamate antagonists.125
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
Initial efforts to characterize κ opioid receptors by radioligand binding were impeded by the absence of selective ligands. The affinities of the prototype κ opioid agonist (—)ethylketazocine at the μ and δ opioid receptors relative to that at the κ receptor are estimated to be 0.8 and 0.2, respecitvely (Kosterlitz et al., 1981). The presence of a distinct κ opioid receptor binding site in guinea pig brain was demonstrated by the very low affinities of the μ receptor agonist DAMGO (Ki = 4960 nM) and δ receptor agonist DADLE (Ki = 27900 nM) for the high affinity site labeled by [3H](±)ethylketazocine and by the limited ability of dihydromorphine and DADLE to protect [3H](±)ethylketazocine binding sites from alkylation by phenoxybenzamine (Kosterlitz et al., 1981). Interference due to a μ and δ receptor binding by radioligands with high affinity for κ receptors can be blocked by the presence of unlabeled ligands selective for these two opioid receptor types (Chang et al., 1981; Magnan et al., 1982). However, this approach to the investigation of κ receptor binding can produce different results depending on the radioligand used. The binding site density (Bmax value) measured for [3H]diprenorphine (109 fmol/mg protein) is significantly greater than that (39 fmol/mg protein) measured for [3H](±) ethylketazocine under the same conditions where μ and δ receptors are blocked with selective ligands (Weyhenmeyer and Mack, 1985). The residual binding of [3H]diprenorphine and [3H](±)ethylketazocine in the presence of the blocking ligands is naloxone displaceable, suggesting that the difference in binding site populations could represent binding to different κ receptor populations; this is assuming that there are only three opioid receptor types.
An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease
Published in Expert Opinion on Pharmacotherapy, 2021
Zoe M. Lipman, Gil Yosipovitch
Prior to our understanding of the opioid system’s role in pruritus, activation of peripheral KORs has been widely shown to reduce transmission of pain. Nalbuphine, the first known KOR agonist/MOR antagonist, has shown success in treating both pain and itch (including uremic pruritus); however, its mu-antagonism and action in the CNS can lead to negative side effects like depression and restlessness [27]. The first kappa-selective KOR agonist was ketocyclazocine (the namesake of the kappa opioid receptor), a benzomorphan [28]. Early studies of benzomorphans like ketocyclazocine and ethylketazocine, nalorphine, Mr2023, and pentazocine revealed analgesic effects in both mice and dogs against both chemical and pressure stimuli, but also revealed unwanted side effects like sedation and ataxia. These side effects were assumed to be due to the drugs’ residual effects on other opioid receptors like mu- and delta- [29]. Arylacetamide enadoline (Cl-977) was also a potent antinociceptive agent that displayed a similar binding affinity for KORs as the benzomorphan ethylketocyclazocine but with increased KOR selectivity, and in turn, produced less MOR-related sedative side effects [30]. However, despite its analgesic potential, later studies showed that it induced potent diuresis as well as dose-limiting neuropsychiatric effects [31].