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: Glutamate transporter subtype 1 (GLT-1) activation is a promising - and understudied - approach for managing aspects of morphine tolerance caused by increased glutamatergic transmission. Identification of beta-lactam antibiotics as pharmaceuticals which activate GLT-1 transporters prompted us to hypothesize that repeated beta-lactam antibiotic (ceftriaxone) administration blocks development of tolerance to morphine antinociception through GLT-1 activation. Here, we injected rats with morphine (10mg/kg, s.c.) twice daily for 7 days to induce tolerance and used the hot-plate assay to determine antinociception on days 1, 4 and 7 of repeated morphine administration. Ceftriaxone and a selective GLT-1 transporter inhibitor dihydrokainate (DHK) were co-administered with morphine to determine if GLT-1 activation mediated the ceftriaxone effect. Tolerance was present on days 4 and 7 of repeated morphine administration. Ceftriaxone (50, 100 or 200mg/kg, i.p.) administration dose-dependently blocked development of morphine tolerance. DHK (10mg/kg, s.c.), administered 15 min before each morphine injection, prevented inhibition of morphine tolerance by ceftriaxone (200mg/kg, i.p.). These results identify an interaction between ceftriaxone and morphine in opioid-tolerant rats and suggest beta-lactam antibiotics preserve analgesic efficacy during chronic morphine exposure.Drug and alcohol dependence 12/2009; 107(2-3):261-3. DOI:10.1016/j.drugalcdep.2009.10.010 · 3.28 Impact Factor
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ABSTRACT: Previous studies have demonstrated that some anticonvulsant drugs can modulate tolerance to the opioid analgesia. In the present study, the effects of lamotrigine (LTG) on the development and expression of tolerance to the morphine-induced antinociception were evaluated using tail-flick test. To assess the LTG effects on tolerance development, the animals received LTG (3, 10 or 30 mg/kg; i.p.), 30-min prior to morphine (50 mg/kg; s.c.) administration during tolerance induction period once daily for 3 days. Also, to evaluate the effects of LTG on tolerance expression, different doses of LTG were administered 30-min before challenge dose of morphine (4 mg/kg; s.c.) following morphine-induced tolerance. In each experiment the antinociceptive response to the challenge dose of morphine was evaluated before (on day 1) and after tolerance induction (on day 4) every 30-min till 2 h by tail-flick test. Furthermore, the analgesic effect of various doses of LTG alone or with the challenge dose of morphine was evaluated as well. The results showed that LTG at the doses of 10 and 30 mg/kg could inhibit the development of tolerance. Also, LTG at the dose of 30 mg/kg attenuated the expression of morphine-induced tolerance. LTG alone injection was associated significantly with higher latency period when compared to the control group. Moreover, LTG (10 and 30 mg/kg) significantly enhanced antinociceptive effect of morphine challenge dose in non-tolerant animals. These data indicated that, while LTG can attenuate both development and expression of morphine-induced tolerance, it can enhance morphine-induced antinociception. These effects may have important clinical implications.Brain research 08/2009; 1291:32-9. DOI:10.1016/j.brainres.2009.07.014 · 2.83 Impact Factor
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ABSTRACT: Although mechanisms underlying ultra-low dose naloxone-induced analgesia have been proposed, possible interactions with glutamatergic transmission and glial cell activation have not been addressed. In the present study, we examined the effect of ultra-low dose naloxone on spinal glutamatergic transmission and glial cell activity in rats chronically infused with morphine. In male Wistar rats, intrathecal morphine infusion (15microg/h) for 5days induced (1) antinociceptive tolerance, (2) downregulation of glutamate transporters (GTs) GLT-1, GLAST, and EAAC1, (3) increasing of NMDA receptor (NMDAR) NR1 subunit expression and phosphorylation, (4) upregulation of protein kinase C gamma (PKCgamma) expression, and (5) glial cell activation. On day 5, morphine challenge (15microg/10microl) caused a significant increase in the concentration of the excitatory amino acids (EAAs) aspartate and glutamate in the spinal CSF dialysates of morphine-tolerant rats. Intrathecal co-infusion of ultra-low dose naloxone (15pg/h) with morphine attenuated tolerance development, reversed GTs expression, inhibited the NMDAR NR1 subunit expression and phosphorylation, and PKCgamma expression, inhibited glial cell activation, and suppressed the morphine-evoked EAAs release. These effects may result in preservation of the antinociceptive effect of acute morphine challenge in chronic morphine-infused rats. Ultra-low dose naloxone infusion alone did not produce an antinociceptive effect. These findings demonstrated that attenuation of glutamatergic transmission and neuroinflammation by ultra-low dose naloxone co-infusion preserves the lasting antinociceptive effect of morphine in rats chronically infused with morphine.Pharmacology Biochemistry and Behavior 08/2010; 96(2):236-45. DOI:10.1016/j.pbb.2010.05.012 · 2.82 Impact Factor