Quantitative immunolocalization of mu opioid receptors: regulation by naltrexone

Unterwald, Ellen M.; Antón, Benito; To, Trang; Lam, Hoa A.; Evans, Christopher J.

doi:10.1016/s0306-4522(97)00659-3

Cited by 51 publications

(32 citation statements)

References 32 publications

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“…Chronic treatment with opioid antagonists, such as naloxone or naltrexone, induces up-regulation of opioid receptor density (Bmax) in cell cultures as well as in animal models. Receptor up-regulation was determined by radioligand binding, autoradiography and quantitative immuno-localization (Lesscher et al, 2003;Unterwald et al, 1998;Yoburn et al, 1989;Zadina et al, 1993;Zukin and Tempel, 1986). Antagonist-induced MOP up-regulation results in an increase in mu agonist-stimulated G-protein activation (Narita et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…It has been found that, after antagonist treatment, the number of binding sites is increased without change in the total receptor number in some brain regions, whereas in other regions, receptors binding sites are increased with concomitant changes in total receptor number. This was assessed in adjacent tissue sections of the brain regions by MOP immunohistochemistry and autoradiography after antagonist administration (Unterwald et al, 1998). The mechanism of chronic opioid antagonist induced up-regulation is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

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Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Onoprishvili

Simon

2007

Brain Research

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We investigated the effects of morphine and other agonists on the human mu opioid receptor (MOP) expressed in M2 melanoma cells, lacking the actin cytoskeleton protein filamin A and in A7, a sub clone of the M2 melanoma cells, stably transfected with filamin A cDNA. The results of binding experiments showed, that after chronic morphine treatment (24 hr) of A7 cells, MOP binding sites were down-regulated to 63% of control, whereas, unexpectedly, in M2 cells, MOP binding was upregulated to 188% of control naïve cells. Similar up-regulation was observed with the agonists methadone and levorphanol. The presence of antagonists (naloxone or CTAP) during chronic morphine treatment inhibited MOP down-regulation in A7 cells. In contrast, morphine-induced upregulation of MOP in M2 cells was further increased by these antagonists. Chronic morphine desensitized MOP in A7 cells, i.e. it decreased DAMGO-induced stimulation of GTPγS binding. In M2 cells DAMGO stimulation of GTPγS binding was significantly greater than in A7 cells and was not desensitized by chronic morphine. Pertussis toxin treatment abolished morphine-induced receptor up-regulation in M2 cells, whereas it had no effect on morphine-induced down-regulation in A7 cells. These results indicate that, in the absence of filamin A, chronic treatment with morphine, methadone or levorphanol leads to up-regulation of MOP, to our knowledge, the first instance of opioid receptor up-regulation by agonists in cell culture.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Onoprishvili

Simon

2007

Brain Research

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“…In addition, post-training manipulation of the opioid system in neonates has been shown to disrupt consolidation of the shock-induced odor preference and yield an odor aversion. Since the amygdala displays one of the highest densities of opioid receptor binding sites (Atweh and Kuhar 1977;Mansour et al 1987;Unterwald et al 1998), this suggests it may have a critical role in the dramatic shift from the preference to avoidance memory when neonatal pups' opioid system is disrupted during consolidation. Furthermore, in the adult, post-training intraamygdala infusion of NTX facilitates consolidation of emotional experiences (McGaugh et al 1988;Quirate et al 1998).…”

Section: Learning and Memory 591mentioning

confidence: 99%

Opioid modulation of Fos protein expression and olfactory circuitry plays a pivotal role in what neonates remember

Roth¹,

Moriceau²,

Sullivan³

2006

Learn. Mem.

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Paradoxically, fear conditioning (odor-0.5 mA shock) yields a learned odor preference in the neonate, presumably due to a unique learning and memory circuit that does not include apparent amygdala participation. Post-training opioid antagonism with naltrexone (NTX) blocks consolidation of this odor preference and instead yields memory of a learned odor aversion. Here we characterize the neural circuitry underlying this switch during memory consolidation. Experiment 1 assessed post-training opioid modulation of Fos protein expression within olfactory circuitry (olfactory bulb, piriform cortex, amygdala). Odor-shock conditioning with no post-training treatment (odor preference) induced significant changes in Fos protein expression in the granule cell layer of the olfactory bulb and anterior piriform cortex. Post-training opioid receptor antagonism (odor aversion) prevented the learning-induced changes in the anterior piriform cortex and also induced significant changes in Fos protein expression in the central nucleus of the amygdala. Experiment 2 assessed intra-amygdala opioid modulation of neonate memory consolidation. Post-training infusion of NTX within the amygdala permitted consolidation of an odor aversion, while vehicle-infused pups continued to demonstrate an odor preference. Overall, results demonstrate that opioids modulate memory consolidation in the neonate via modulating Fos protein expression in olfactory circuitry. Furthermore, these results suggest that opioids are instrumental in suppressing neonate fear behavior via modulating the amygdala.Odor-shock conditioning, a learning paradigm that readily produces fear in adult animals, produces a paradoxical odor preference in rat pups <10 d old (Camp and Rudy 1988;Sullivan et al. 2000a;Roth and Sullivan 2001, 2003Moriceau and Sullivan 2004a). This paradoxical behavior is attributable to a relatively simplistic olfactory learning and memory circuit that incorporates the olfactory bulb, anterior piriform cortex, and an apparent lack of amygdala participation (Sullivan et al. 2000a,b; Moriceau and Sullivan 2004a,b;Roth and Sullivan 2005;Moriceau et al. 2006). Indeed, we have demonstrated that the emergence of learned fear coincides with significant amygdala participation (Sullivan et al. 2000a;Moriceau et al. 2006). We suggest this attenuated aversion learning and potentiated preference learning early in development ensures pups readily learn to approach the maternal odor regardless of the quality of care she provides. Indeed, a recent study from our laboratory has documented this paradoxical odor preference learning within a seminatural nest environment as an odor paired with rough handling from a stressed mother resulted in a preference for that odor (Roth and Sullivan 2005). A similar paradoxical attachment despite caregiver abuse has been demonstrated in other species: chick (Hess 1962), infant dogs (Rajecki et al. 1978), and nonhuman primates (Harlow and Harlow 1965;Maestripieri et al. 1997Maestripieri et al. , 1999.We have previously demonstrated a ...

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“…However, it probably does not reflect a substantial activation of m-opioid receptor protein expression, as indicated by the relatively small increase in m-opioid receptor immunoreactivity observed only after two courses of extended-release naltrexone administration. While the mechanisms responsible for the lack of correlation between the increase in density of m-opioid receptor binding sites and immunoreactivity are not clear, this phenomenon has been previously observed (Unterwald et al, 1995(Unterwald et al, , 1998Castelli et al, 1997). The cumulative results suggest that the increase in m-opioid receptor density is not regulated at the transcriptional level, but reflects recruitment of active mopioid receptors from a pool of spare, sequestered receptors in response to the presence of antagonists.…”

Section: Discussionmentioning

confidence: 72%

“…Brain sections adjacent to those used for receptor binding were processed for m-opioid receptor immunoreactivity (Unterwald et al, 1998). Sections were immersion fixed in 6% paraformaldehyde, 20% sucrose, 20% ethanol, 20% ethylene glycol, and 10% glycerol in 0.05 M phosphate buffer (Jones et al, 1992), then washed in phosphate-buffered saline.…”

Section: Hot-plate Testingmentioning

confidence: 99%

Vivitrex®, an Injectable, Extended-Release Formulation of Naltrexone, Provides Pharmacokinetic and Pharmacodynamic Evidence of Efficacy for 1 Month in Rats

Bartus

Emerich

Hotz

et al. 2003

Neuropsychopharmacol

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While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex s ) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mOpioid receptor density, as measured by [ 3 H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [3 H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in m-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.

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Quantitative immunolocalization of mu opioid receptors: regulation by naltrexone

Cited by 51 publications

References 32 publications

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Opioid modulation of Fos protein expression and olfactory circuitry plays a pivotal role in what neonates remember

Vivitrex®, an Injectable, Extended-Release Formulation of Naltrexone, Provides Pharmacokinetic and Pharmacodynamic Evidence of Efficacy for 1 Month in Rats

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