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This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) during induction of morphine dependence on the severity of physical and psychological dependence and the cerebrospinal fluid (CSF) BDNF levels in morphine-dependent and withdrawn rats. Rats became morphine-dependent by increasing daily doses of morphine for 7 days, along with ANA-12 injection. Then, rats were tested for the severity of physical dependence on morphine (spontaneous withdrawal signs), anxiety-like (the elevated plus maze), depressive-like (sucrose preference test) behaviors after spontaneous morphine withdrawal. Also, the CSF BDNF levels were assessed 2 h after the last dose of morphine and day 13 after morphine withdrawal in morphine-dependent and withdrawn rats. We found that the morphine withdrawal signs were significantly higher in morphine dependent rats receiving ANA-12 on days of 5-7 after morphine withdrawal, also ANA-12 exacerbated overall dependence severity. While, the percentage of time spent in the open arms and sucrose preference were higher in morphine-dependent rats receiving ANA-12 than morphine-dependent rats receiving saline. Also, the ANA-12 injection decreased the CSF BDNF levels following morphine dependence, while increased it after morphine withdrawal. We conclude that the ANA-12 exacerbated the severity of physical morphine dependence but attenuated the anxiety/depressive-like behaviors in morphine-dependent and withdrawn rats. Also, ANA-12 injection was able to reverse the changes in the CSF BDNF levels. Therefore, ANA-12 is not more likely to complete treatment for opiate addiction.

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Optimal therapeutics to deal with high relapse rates when discontinued is urgent for opioid dependence treatments. Endogenous endomorphin-2 (EM2) level in the central nervous system (CNS) down-regulates obviously after sustained morphine exposure, which suggested that to up-regulate the EM2 level could be a novel method for reinstatement. But the clinical applications of EM2 through conventional administration are limited owing to its short half-life. In our study, we engineered an EM2 gene to achieve the sustained release of EM-2 in CNS by utilizing a signal peptide of mouse growth factor for out-secreting EM2 and a deficient adenovirus as the vector. By intrathecally injecting engineering EM2 gene, a sustained increase of EM2 concentration in the cerebral spinal fluid (CSF) was observed along with a reduction of CPP scores. Also, the activation of astrocytes was suppressed in the hippocampus. In summary, this study provides evidence and reference for using intraspinal gene therapy with a combination of mouse growth factor and EM2 to treat morphine reinstatement.

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Introducción: La morfina, como otros opiáceos y las drogas de abuso, tiene la capacidad de modificar la plasticidad cerebral de las áreas que regulan la morfología neuronal de las dendritas y espinas, que son el sitio primario de sinapsis excitatorias en regiones cerebrales que regulan funciones de incentivo motivación, recompensa y aprendizaje. Objetivo: En la presente revisión se analizan aspectos del impacto del uso de la morfina durante los periodos prenatales del desarrollo cerebral y las consecuencias a largo plazo en murinos, para relacionar estos efectos que ocurren en el humano neonato y adulto. Desarrollo: La exposición repetida a la morfina en el tratamiento del dolor en enfermos terminales produce cambios a largo plazo en la densidad postsináptica de sitios (dendritas y espinas) en áreas sensibles del cerebro, como la corteza prefrontal y el sistema límbico (hipocampo, amígdala), así como en los núcleos caudado y accumbens. Este artículo revisa los mecanismos celulares implicados, principalmente de los receptores dopaminérgicos y glutamatérgicos, así como la plasticidad sináptica lograda por los cambios en las dendritas y espinas en esta área. Conclusiones: Las acciones de la morfina durante el desarrollo del cerebro y también en el cerebro adulto producen alteraciones en la plasticidad de sitios excitatorios postsinápticos, áreas del cerebro que están implicadas en las funciones del sistema límbico (la recompensa y el aprendizaje). Se necesitan más estudios sobre la plasticidad en las dendritas y espinas en sus moléculas de señalización, tales como el calcio, con el fin de mejorar el tratamiento de la adicción

Introduction: Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. Objective: In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. Development: Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. Conclusions: The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction

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This study was designed to investigate the effect of acute and chronic intrathecal (i.t.) injection of gabapentin (GBP) on the antinociceptive effect of morphine and tolerance development using a tail-flick latency test. Levels of excitatory amino acids (EAA) in i.t. CSF dialysates were also measured by high performance liquid chromatography. Male Wistar rats were implanted with either one or two i.t. catheters for drug injection or pump infusion and with a microdialysis probe for CSF dialysate collection. The effect of acute GBP (10 microg i.t.) injection on the morphine dose response was examined in both naïve rats and rats made tolerant by continuous infusion of morphine (15 microg/h i.t.) for 5 days. At such a low dose (10 microg i.t.), GBP did not enhance morphine's antinociception in naïve rats. In morphine-tolerant rats, however, acute GBP (10 microg i.t.) injection potentiated morphine's antinociception and yielded a 14.6-fold shift in morphine's dose-response curve. When GBP (10 microg/h i.t.) was co-infused with morphine (15 microg/h i.t.) to examine its effect on the development of morphine tolerance, GBP attenuated the development of morphine tolerance. The effect of GBP and morphine on CSF glutamate and aspartate levels was examined in naïve rats, and the effect of morphine challenge on CSF glutamate and aspartate levels was examined in rats previously infused for 5 days with morphine alone or morphine plus GBP. Acute injection of GBP (10 microg i.t.), morphine (50 microg i.t.), or GBP (10 microg i.t.) followed by morphine (50 microg i.t.) 30 min later had no significant effect on CSF EAA concentration in naïve rats; however, in tolerant rats, morphine challenge (50 microg i.t.) increased aspartate and glutamate levels to 221 +/- 22% and 296 +/- 43%, respectively, of those before morphine challenge, and this phenomenon was inhibited by GBP co-infusion. Our results show that GBP, at a dose without enhanced effect on morphine's antinociception in naïve rats, not only potentiates morphine's antinociceptive effect in morphine-tolerant rats but also attenuates the development of morphine tolerance. The mechanism of the effect of GBP on morphine tolerance might be via suppression of the EAA concentration in spinal CSF dialysate.

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We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in morphine-tolerant rats after morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited morphine tolerance and the morphine challenge-induced EAAs increase after long-term morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. morphine (15 microg/h), saline (1 microl/h), DEX (2 microg/h), or DEX (2 microg/h) plus morphine (15 microg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after morphine challenge (50 microg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD50 (analgesic dose) on day 5 was 1.33 microg in saline-infused rats, 83.84 microg in morphine-tolerant rats, and 10.15 microg in DEX plus morphine co-infused rats. Single DEX (2 microg, i.t.) injection did not enhance morphine's antinociceptive effect in either naïve or morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after morphine challenge, an increase in glutamate and aspartate (284+/-47% and 201+/-18% of basal) concentration was observed, and morphine lost its antinociceptive effect (maximum percent effect, MPE = 41+/-12%), whereas DEX/morphine co-infusion inhibited morphine-evoked EAA increase with a MPE = 97+/-2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204+/-20% of basal). DEX co-infusion inhibits the morphine-challenge induced EAA increase and prevents the loss of morphine's antinociceptive effect after long-term morphine infusion.

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Rats were rendered dependent on morphine by repeated injections of morphine, in increasing doses for 14 days and sacrificed. Levels of peptides in the dorsal spinal cord and dorsal root ganglia were analyzed in rats decapitated 2 hr, 24 hr (acute abstinent) or 7 days (late abstinent) respectively, after the last injection of drug. Dynorphin A was significantly decreased in rats abstinent for 24 hr, while dynorphin B remained unaffected. Substance P and CGRP, both putative transmitters in nociceptive primary afferent neurones, and partly existing together in the same neurone, were affected differently. Significantly less substance P but unchanged levels of CGRP were detected in rats abstinent for 24 hr, while on the other hand, CGRP but not levels of substance P, were increased 2 hr after the final injection. In dorsal root ganglia, levels of substance P were lower at 2 hr, while levels of CGRP were unaffected. In late (7 days) abstinence, no effect of opiate on any peptide was detected.

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Yang et al. have isolated from bovine brain an octapeptide, FLFQPQRF-NH2 (F-8-F-NH2), with certain antiopiate properties. Malin et al. previously found that ICV injection of this peptide could precipitate an opiate abstinence syndrome in dependent rats. RIA revealed significantly higher levels of F-8-F-NH2 immunoreactivity in CSF withdrawn from the cisterna magna of morphine-dependent rats as opposed to CSF withdrawn from sham-implanted controls. ICV infusion of IgG from antiserum against F-8-F-NH2 significantly reduced the number of abstinence signs subsequently precipitated by naloxone in morphine-dependent rats.

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Cerebrospinal fluid (CSF) was withdrawn from opiate-dependent rats following six hours of abstinence. It was infused into the third ventricle of opiate-dependent rats, precipitating immediate abstinence signs. The effect was similar to that of infusing the opiate antagonist naloxone, suggesting that opiate-dependent organisms may secrete an endogenous opiate antagonist substance. CSF withdrawn from non-dependent rats failed to precipitate an abstinence syndrome in morphine-dependent recipients. Conversely, CSF withdrawn from opiate-dependent rats following six hours of abstinence failed to precipitate an abstinence syndrome in non-dependent recipients. The active factor in the CSF is probably a peptide since it is filterable through a 10,000 MW filter and its activity is destroyed by three different proteolytic enzymes.

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