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Leukemia inhibitory factor (LIF) potentiates antinociception activity and inhibits tolerance induction of opioids
No full textBackground: The efficacy of opioids typically decreases after long-term use owing to the development of tolerance. Glial activation and the upregulation of proinflammatory cytokines are related to the induction of tolerance. We investigated the effect of leukemia inhibitory factor (LIF) on morphine analgesia and tolerance.
Methods: LIF concentrations in rat spinal cords were measured by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) after morphine administration. LIF distribution was examined using confocal microscopy. To evaluate the effects of LIF on morphine analgesia and tolerance, LIF was intrathecally administered 30 min before morphine injection. The analgesic effect of morphine was evaluated by measuring tail-flick latency. Human LIF concentrations from the cerebrospinal fluid (CSF) of opioid tolerant patients were also determined by specific ELISA.
Results: Chronic morphine administration upregulated LIF concentrations in rat spinal cords. Intrathecal injection of LIF potentiated the analgesic action of morphine. Patch clamp recording of spinal cord slices showed that LIF enhanced DAMGO ([D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin)-induced outward potassium current. The development of tolerance was markedly suppressed by exogenous LIF, whereas neutralizing the endogenously released LIF with anti-LIF antibodies accelerated the tolerance induction. Moreover, LIF concentrations in the CSF of opioid-tolerant patients were higher than those in the opioidnaive controls.
Conclusions: Intrathecal administration of LIF potentiated morphine antinociceptive activity and attenuated the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other proinflammatory cytokines. LIF might be a novel drug candidate for inhibiting opioid tolerance induction
Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at alpha 6 subunit-containing GABA(A) receptors in the cerebellum
No full textHispidulin is a flavonoid we isolated from Clerodendrum inerme, an herb that effectively remitted a case of intractable motor tic disorders. Hispidulin was shown to be a positive allosteric modulator (PAM) of GABA(A) receptors, including the alpha(6) subunit-containing subtype (alpha(6)GABA(A)R) that is predominantly expressed in cerebellar granule cells and insensitive to diazepam.
We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders.
Hispidulin significantly inhibited methamphetamine-induced hyperlocomotion (MIH) at i.p. doses without affecting apomorphine-induced hyperlocomotion and stereotypy behaviors or having significant benzodiazepine-like effects (BZLE), including sedation, anxiety, and motor impairment. When given by intracerebellar (i.c.b.) microinjection, hispidulin also alleviated MIH and this effect was prevented by i.c.b. coadministration of furosemide, an alpha(6)GABA(A)R antagonist, and mimicked by i.c.b. Ro 15-4513, an alpha(6)GABA(A)R PAM. Conversely, i.c.b. diazepam did not affect MIH while it reduced MIH at i.p. doses having significant BZLE. In a screening assay for 92 neurotransmitter receptors/degradation enzymes/transporters, hispidulin displayed significant (> 50 % inhibition of radiolabeled ligand binding at 10 mu M) binding affinity only at the benzodiazepine binding site of GABA(A)Rs (IC50 0.73 +/- 1.78 mu M) and catecholamine-o-methyl-transferase (COMT) (IC50 1.32 mu M). OR-486, a more potent COMT inhibitor than hispidulin, did not affect MIH.
It is suggested that hispidulin alleviates MIH via acting as a PAM of cerebellar alpha(6)GABA(A)Rs, but not through COMT inhibition or affecting dopamine receptor responsiveness. Thus, selective alpha(6)GABA(A)R PAMs may have the potential to be a novel treatment for hyperdopaminergic disorders
A new test for one-way ANOVA with funcational data and application to ischemic heart screening
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Quantitative uniqueness estimates for second order elliptic equations with unbounded drift
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