Systemic Administration Of Baclofen Research Articles

Differential effects of baclofen and oxytocin on the increased ethanol consumption following chronic psychosocial stress in mice

Chronic stress is known to enhance the susceptibility for addiction disorders including alcoholism. While these findings have been recapitulated in animal models, the majority of these studies have utilized non-social rather than social stress paradigms; the latter of which are believed to be more relevant to the human situation. Therefore, the major aim of this study was to investigate, if 14 days of chronic subordinate colony housing (CSC), a pre-clinically validated psychosocial stress paradigm relevant for human psychiatric and somatic disorders, enhances ethanol (EtOH) consumption in male mice. To assess this, we employed the well-established two-bottle free-choice paradigm where mice were given access to water and 2, 4, 6 and 8% EtOH solutions (with the concentrations increasing each fourth day) following termination of the stress procedure. After 14 days of CSC, stressed mice consumed significantly more EtOH at all concentrations tested and displayed increased EtOH preference at concentrations of 6 and 8%. This effect was not due to an altered taste preference in CSC mice as assessed by saccharine- and quinine-preference tests, but was accompanied by increased anxiety-related behavior. Systemic administration of baclofen (2.5 mg/kg) or oxytocin (OXT; 10 mg/kg) reduced the EtOH intake in single housed control (baclofen, OXT) and CSC (baclofen) mice, whereas intracerebroventricular OXT (0.5 μg/2 μl) was ineffective in both groups. Taken together, these results suggest that (i) chronic psychosocial stress enhances EtOH consumption, and (ii) baclofen and OXT differentially affect EtOH intake in mice.

Effect of a selective GABA B receptor agonist baclofen on the μ-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects

The management of excessive adverse effects of opioids is a major clinical problem. The present study was undertaken to investigate the effect of a selective γ-aminobutyric acid (GABA) B receptor agonist baclofen on the μ-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Either morphine or fentanyl produced a dose-dependent antinociceptive effect in both ferrets using Randall-Selitto test and mice using tail-flick test. Under these conditions, pretreatment of baclofen produced an additive antinociception induced by morphine or fentanyl. Furthermore, the augmentation of antinociception induced by systemic administration of baclofen with morphine or fentanyl was completely abolished by either i.c.v. or i.t. pretreatment with the selective GABA B receptor antagonist CGP 35348 in mice. We next investigated the emetic response induced by μ-opioid receptor agonist in ferrets. Morphine at lower doses than that used for antinociceptive assay produced both retching and vomiting, whereas fentanyl failed to produce the retching and vomiting in ferrets. Here we reported for the first time that baclofen significantly suppressed the retching and vomiting induced by morphine, indicating the involvement of GABA B receptor in emetic control pathway. Furthermore, baclofen also inhibited place preference elicited morphine or fentanyl in rats. Taken together, these results suggest that co-administration of baclofen with μ-opioid receptor agonist produced a potentiation of antinociceptive effect, whereas an untoward effect was completely blocked.

GABA B receptor-mediated effects on expression of c-Fos in rat trigeminal nucleus following high- and low-intensity afferent stimulation.

We examined the effects of systemic administration of a GABA(B) receptor agonist, baclofen, or antagonist, phaclofen, on the expression of c-Fos protein induced 3h after electrical stimulation of the trigeminal ganglion at low (0.1 mA) or high intensities (1.0 mA) in the urethane-anesthetized rat. In saline-treated rats, 10 min stimulation of the trigeminal ganglion induced c-Fos-immunopositive neurons throughout the full extent of the ipsilateral superficial layers of the trigeminal nucleus caudalis, and dorsal or dorsomedial part of the nuclei rostral to obex (trigeminal nucleus principalis, dorsomedial nucleus of trigeminal nucleus oralis and dorsomedial nucleus of trigeminal nucleus interpolaris). Animals stimulated at 1.0 mA induced a significantly higher number of labeled neurons in all the trigeminal sensory nuclei than animals stimulated at 0.1 mA. In rats treated with 20mg/kg i.p. baclofen and stimulated at 0.1 mA, the numbers of Fos-positive neurons in all the trigeminal sensory nuclei were significantly decreased compared to saline-treated controls. After stimulation at 1.0 mA in rats treated with baclofen, the numbers of Fos-positive neurons in all the trigeminal sensory nuclei were also significantly decreased. In rats treated with 2mg/kg i.p. phaclofen and stimulated at 1.0 mA, the numbers of Fos-positive neurons were significantly increased in all the trigeminal sensory nuclei. However, after stimulation at 0.1 mA in rats treated with phaclofen, the numbers of Fos-positive neurons were significantly decreased in the superficial layers and magnocellular zone of trigeminal nucleus caudalis and dorsomedial nucleus of trigeminal nucleus oralis. These results indicate that the expression of c-Fos in the trigeminal sensory nucleus is differentially regulated through GABAB receptors in a manner that is dependent on the nucleus and the type of primary afferents that are activated by different stimulus intensities. Systemic administration of baclofen could inhibit both nociceptive and non-nociceptive sensory activity in the trigeminal sensory nucleus. Systemic administration of phaclofen could enhance nociceptive sensory activity but not non-nociceptive activity.

Systemic administration of baclofen and the GABAB antagonist, CGP 35348, does not affect GABA, glutamate or aspartate in microdialysates of the striatum of conscious rats.

Previous in vitro experiments have shown that the GABAB agonist, baclofen, and the antagonist, CGP 35348, respectively, decrease and increase the autoreceptor-mediated release of GABA in brain slices and synaptosomes. Since it is not clear whether these autoreceptors are operative in vivo, an attempt was made to reproduce these results in brain dialysis experiments, knowing that only positive results would permit a conclusion in view of the doubts expressed in the literature with respect to the origin of extracellular GABA. Because of older reports of an inhibitory action of baclofen on the in vitro release of glutamate, which might be ascribed to the action of presynaptic GABAB heteroreceptors, extracellular glutamate and aspartate were also measured. Neither (-)-baclofen, administered systemically at a dose of 20 mg/kg i.p., nor the GABAB antagonist, CGP 35348 (300 mg/kg i.p.) had significant effects on basal overflow of GABA, glutamate, or aspartate nor on that evoked by 100 mmol/l K+ in the striatum of the conscious, freely moving rat. To ascertain this result, (-)-baclofen was also administered between two K+ stimulations, so that the first stimulation could serve as an intraindividual control of the second. The compound did not significantly affect K+ evoked overflow of any of the three transmitter amino acids under these conditions. It must be emphasized that these data do not exclude the operativity of presynaptic GABAB auto- and heteroreceptors in vivo. They only suggest that this question must, in all probability, be addressed by other techniques than brain dialysis.

Analgesia produced by microinjection of baclofen and morphine at brain stem sites

Microinjection of either baclofen (1.5 μg) or morphine (2.5 μg), in equimolar doses (14 mM), at sites located in the caudal periaqueductal gray (PAG) resulted in a delay in tail flick latency (analgesia). The relative analgesic potency of baclofen among caudal PAG sites, however, did not correlate with that of morphine. Application of either drug into the caudal aspect of the cerebral aqueduct also produced analgesia, but neither agent caused analgesia when applied at PAG sites rostral to the interaural line. Baclofen alos produced analgesia when microinjected in the lower brain stem at sites lateral to the midline in or near the nucleus gigantocellularis, but did not produce analgesia when applied on the midline at sites located within or near the raphe magnus. Conversely, morphine produced analgesia when applied locally at midline sites but not at sites located lateral to the midline. These data suggest that the analgesia produced by systemic administration of baclofen and morphine involves activation of different neuronal substrates.