Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone

Iijima, Ikuo; Minamikawa, Jun‐ichi; Jacobson, Arthur E.; Brossi, Arnold; Rice, Kenner C.; Klee, Werner A.

doi:10.1021/jm00202a018

Cited by 152 publications

(89 citation statements)

References 5 publications

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“…Interestingly, studies in the Parkinson's disease model, in particular, have shown that both NAL stereoisomers are equally neuroprotective Liu et al, 2002). In contrast, only (−)-naloxone isomer binds to and antagonizes opioid receptors, while the (+)-enantiomer is inert in this regard (Iijima et al, 1978;Marcoli et al, 1989). Further investigations have now fully dissociated the neuroprotective effect of NAL from its opioid receptor signaling (Liu and Hong, 2003).…”

Section: Discussionmentioning

confidence: 99%

The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis

Prow¹,

Irani²

2007

Experimental Neurology

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Spread of neuroadapted Sindbis virus (NSV) to motor neurons (MN) of the spinal cord (SC) causes severe hind limb weakness in C57BL/6 mice and models the paralysis that can accompany alphavirus and flavivirus encephalomyelitis in humans. The fate of spinal MN dictates the severity of NSVinduced paralysis, and recent data suggest that MN damage can occur indirectly via the actions of activated microglial cells. Because the opioid receptor antagonist, naloxone (NAL), blocks microglial-mediated neurodegeneration in other models, we examined its effects during NSV infection. Drug treatment prevented paralysis and enhanced the survival of MN without altering NSV tropism, replication, or clearance from SC tissue. Further studies showed that NAL most effectively inhibited paralysis in a 72-hour window after NSV challenge, suggesting that the drug inhibits an early event in SC pathogenesis. Histochemical studies demonstrated that NAL blocked early microglial activation in SC tissue sections, and protein assays showed that the early induction of pathogenic IL-1β was blunted in SC homogenates. Finally, loss of glutamate transporter-1 (GLT-1) expression in SC, an astrocyte glutamate reuptake protein responsible for lowering toxic extracellular levels of glutamate and preventing MN damage, was reversed by NAL treatment. This GLT-1 loss proved to be highly IL-1β-dependent. Taken together, these data suggest that NAL is neuroprotective in the SC by inhibiting microglial activation that, in turn, maintains normal astrocyte glutamate homeostasis. We propose that drugs targeting such microglial responses may have therapeutic benefit in humans with related viral infections.

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Section: Discussionmentioning

confidence: 99%

The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis

Prow¹,

Irani²

2007

Experimental Neurology

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“…This receptor is therefore tentatively defined as the naloxonesensitive sigma receptor, which resembles the opiate sigma receptor originally proposed by Martin et al (1976). (+)-Naloxone, an enantiomer of the non-selective µ-opioid receptor antagonist naloxone, has been shown not to have any affinity for µ-opioid receptors or block µ-opioid mediated analgesia (Iijima et al, 1978b). (+)-Naloxone and the sigma receptor antagonist BD1047 were then used as the receptor antagonist to determine if the antianalgesia induced by (+)-morphine or (−)-morphine is mediated by the activation of the naloxonesensitive sigma receptors.…”

Section: Pretreatment With (+)-Morphine or (−)-Morphine Attenuates Thmentioning

confidence: 99%

Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

Hong

Tseng

2007

European Journal of Pharmacology

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We have previously demonstrated that (+)-morphine and (−)-morphine given spinally stereoselectively attenuate the spinally-administered (−)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia (Wu et al., 2005). Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (−)-morphine also stereoselectively attenuates the systemic (−)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (−)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01-10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneouslyadministered (−)-morphine (5 mg/kg). Pretreatment with (−)-morphine (0.01-1.0 mg/kg) given subcutaneously also attenuates the (−)-morphine-produced tail-flick inhibition. The ED 50 values for (+)-morphine and (−)-morphine for inhibiting the (−)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 µg/kg, respectively. The attenuation of the (−)-morphineproduced tail-flick inhibition induced by (+)-morphine or (−)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/ kg) given subcutaneously also attenuates (−)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (−)-morphine given systemically in attenuating the systemic (−)-morphine-produced antinociception and the antianalgesic effect of (+)-morphine and (−)-morphine is mediated by activation of the naloxonesensitive sigma receptor.

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“…This distinction between the effect of (1)-naloxone on locomotor activity induced by heroin/6-AM and morphine may suggest that heroin/6-AM involves non-ORs/targets such as TLR4 in a different manner than morphine. However, a more likely explanation is a nonspecific effect of high doses of (1)-naloxone on ORs, since high concentrations of (1)-naloxone/naltrexone will also antagonize ORs, although with approximately 2500-10,000 times lower binding affinities (Iijima et al, 1978;Theberge et al, 2013). By extrapolating from Table 2, we can calculate that brain concentrations after 50 mg/kg (1)-naloxone were approximately 3500-5000 times higher than after 0.01 mg/kg (2)-naloxone, indicating possible OR antagonism.…”

Section: Discussionmentioning

confidence: 99%

“…(1)-Naloxone hydrochloride was synthesized (Iijima et al, 1978) by Dr. Kenner C. Rice (National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD). The commercial suppliers reported purities .…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies implied that TLR4 signaling contributes to opioid reinforcement, reward, and withdrawal (Hutchinson et al, 2010(Hutchinson et al, , 2012Theberge et al, 2013). As opposed to ORs, which are stereoselective in their binding properties and thus preferentially bind (2)-isomers of their antagonists such as naloxone (Iijima et al, 1978), TLR4 signaling can be antagonized by both (1) and (2)-isomers of naloxone (and naltrexone) (Hutchinson et al, 2008(Hutchinson et al, , 2010Wang et al, 2016). Blockade of TLR4 signaling by (1)-naloxone was previously reported to suppress morphineinduced striatal dopamine release and conditioned placed preference (CPP) and to reduce remifentanil self-administration in rats (Hutchinson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

Eriksen

Andersen

Boix

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (1)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (2)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (1) and (2)-naloxone in the blood and brain. We found that (2)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (1)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (2)-naloxone reached higher levels than those of (1)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling.

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Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone

Cited by 152 publications

References 5 publications

The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis

The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis

Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

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