Neuroscience
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The aims of this project were to investigate whether inflammation in the orofacial muscle alters mu opioid receptor (MOR) mRNA and protein expressions in trigeminal ganglia (TG), and to assess the contribution of peripheral MORs under acute and inflammatory muscle pain conditions. mRNA and protein levels for MOR were quantified by reverse-transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively, from the TG of naïve rats, and compared with those from the rats treated with complete Freund's adjuvant (CFA) in the masseter. TG was found to express mRNA and protein for MOR, and CFA significantly up-regulated both MOR mRNA and protein by 3 days following the inflammation. The MOR protein up-regulation persisted to day 7 and returned to the baseline level by day 14. ⋯ DAMGO pre-treatment in the contralateral masseter did not attenuate MPC. The same doses of DAMGO administered into CFA-inflamed rats, however, produced a greater attenuation of both MPC and AUC of HS-evoked nocifensive responses. These results demonstrated that activation of peripheral MOR provides greater anti-nociception in inflamed muscle, and that the enhanced MOR effect can be partly explained by significant up-regulation of MOR expression in TG.
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Although codeine is the most prominent and centrally acting antitussive agent, the precise sites and mode of its action have not been fully understood yet. In the present study, we examined the effects of codeine on synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS), which is the first central relay site receiving tussigenic afferent fibers, by using whole-cell patch-clamp recordings in guinea-pig brainstem slices. Codeine (0.3-3 mM) significantly decreased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of the tractus solitarius in a naloxone-reversible and concentration-dependent manner, but it had no effect on the decay time of evoked EPSCs (eEPSCs). ⋯ The inward current induced by application of AMPA remained unchanged after codeine application. A voltage-sensitive K+ channel blocker, 4-aminopyridine (4-AP) attenuated the inhibitory effect of codeine on eEPSCs. These results suggest that codeine inhibits excitatory transmission from the primary afferent fibers to the second-order NTS neurons through the opioid receptors that activate the 4-AP sensitive K+ channels located at presynaptic terminals.
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Comparative Study
Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice.
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride can block the formation of ALLO and other GABAergic neurosteroids and also reduce certain effects of EtOH. Treatment with finasteride during chronic EtOH exposure decreased EtOH withdrawal severity and blood EtOH concentrations (BECs), suggesting an additional effect of finasteride on EtOH pharmacokinetics. ⋯ Finasteride did not alter BECs, EtOH clearance, estradiol, or corticosterone concentrations in a manner that appeared to contribute to the sex difference in finasteride's effect on acute EtOH withdrawal severity. These findings suggest that male and female C57BL/6J and DBA/2J mice differ in their sensitivity to changes in ALLO or other GABAergic neurosteroid levels during acute EtOH withdrawal. Sex differences in the modulation of GABAergic 5alpha-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.
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The central piriform cortex (cPC) is considered to be critically involved in the generation and propagation of kindled seizures. Our previous study found that low-frequency stimulation (LFS) of the cPC inhibits the development process of amygdala kindling. In this study, we determined whether unilateral LFS of the cPC had an inhibitory effect on amygdaloid-kindled seizures in Sprague-Dawley rats. ⋯ On the other hand, LFS of the ipsilateral cPC significantly increased the afterdischarge threshold and further increased the differences of current intensity between afterdischarge threshold and generalized seizure threshold. Our data suggest that LFS of the cPC may be an effective method of inhibiting kindled seizures by preventing both afterdischarge generation and propagation. It provide further evidence that brain regions like the cPC, other than the seizure focus, can serve as targets for deep brain stimulation treatment of epilepsy.
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Sustained exposure to opioid agonists such as morphine increases levels of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn, a response implicated in the development of opioid tolerance and physical dependence. Recent evidence suggests that both the opioid-induced increase in CGRP and the development of opioid physical dependence are suppressed by blockade of spinal cannabinoid (CB1)-receptors. The present study examined whether CB1-receptor activity also has a role in the development of opioid tolerance. ⋯ In animals already exhibiting tolerance to morphine, intervention with AM-251 restored morphine analgesic potency. Co-administration with AM-251 attenuated the morphine-induced increase in CGRP-immunoreactivity in the spinal cord and in DRG cultured neurons. Collectively, the results of this study suggest that activity of endocannabinoids, mediated via CB1-receptors, contributes to both the development and maintenance of opioid tolerance by influencing the opioid-induced increase in spinal CGRP.