Vigabatrin attenuates the development and expression of tolerance to morphine-induced antinociception in mice
ABSTRACT The efficacy of opioids is limited in chronic pain treatment, as a result of development of opioid tolerance. Based on previous demonstration of the effect of anticonvulsant drugs on morphine antinociception, the present study investigated the effects of vigabatrin (VGB) on the development and expression of morphine tolerance in mice. 101 male NMRI mice weighing 20-25 g were used in these experiments. To evaluate the VGB effects on the development or expression of morphine tolerance, animals received VGB (5, 10 or 20 mg/kg; i.p.), 30 min before morphine (50 mg/kg; s.c.) during induction period once daily for 3 days; or 30 min before challenge dose of morphine (5 mg/kg) before and after morphine-induced tolerance, respectively. The analgesic effect of VGB was evaluated at 30-time intervals (30, 60, 90 and 120 min) by tail-flick analgesiometer. The results showed that VGB at the dose of 20 mg/kg significantly attenuated the development and expression of morphine tolerance. Additionally, VGB alone did not affect the tail-flick latency times. Therefore, while VGB alone has no antinociceptive effect, it can prevent the development of morphine tolerance in mice.
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ABSTRACT: Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 µg) was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 µg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity, indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.Journal of Korean medical science 02/2013; 28(2):300-7. DOI:10.3346/jkms.2013.28.2.300 · 1.25 Impact Factor
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ABSTRACT: This paper is the thirty-third consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2010 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).Peptides 12/2011; 32(12):2522-52. DOI:10.1016/j.peptides.2011.09.020 · 2.61 Impact Factor
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ABSTRACT: As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 μg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 μl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 μl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 μg in 5 μl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 min for 120 min after morphine challenge at different temperature (45∼52 °C, respective). Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management.Journal of the Formosan Medical Association 12/2013; 112(12). DOI:10.1016/j.jfma.2013.11.007 · 1.70 Impact Factor