Marcin Maj

Morphine and cocaine influence on CRF biosynthesis in the rat central nucleus of amygdala.

The central nucleus of the amygdala is a CRF-containing limbic brain site which mediates both fear-like and avoidance behaviors; moreover it has been hypothesized that atypical stress responses may contribute to compulsive drug use. Therefore, we studied in rat amygdala the level of CRF mRNA by in situ hybrydization, and the level of the peptide using immunocytochemistry after acute and chronic administration of morphine and cocaine and after their withdrawal. Acute injection of morphine (20 mg/kg i.p.) increased CRF mRNA level, but did not change significantly CRF immunoreactivity in the central nucleus of the amygdala. Chronic morphine administration significantly increased the level of CRF mRNA 3, 24 and 48 h after the last dose. Both, acute and chronic cocaine administration increased CRF mRNA, but the peptide level was decreased only after acute cocaine administration. However, in the late withdrawal (48 h after the last dose of cocaine) both mRNA and the peptide levels tended to decrease. The above data suggest that amygdalar CRF system activity is potently activated after administration of morphine and cocaine, and that activation of this system observed at the time of withdrawal from morphine may be responsible for aversion and anxiety related to these states; therefore a CRF1 receptor may be a target for prospective pharmacotherapies of the withdrawal from abused drugs.

Knockdown of spinal opioid receptors by antisense targeting β-arrestin reduces morphine tolerance and allodynia in rat

The development of morphine tolerance and sciatic nerve injury-induced allodynia after functional knockdown of spinal opioid receptors using antisense oligonucleotides targeting beta-arrestin was investigated. Ineffectiveness of morphine in neuropathic pain suggests an implication of the same mechanism in these two processes. The development of morphine tolerance (10 microg intrathecally (i.th.), every 12 h) was significantly inhibited in rats, which received i.th. beta-arrestin antisenses (2 nM). Acute and chronic (6 days) i.th. administration of antisenses antagonized the allodynia in the rat model of neuropathic pain. Our results demonstrated that i.th. administration of beta-arrestin antisenses delayed development of tolerance to morphine and nerve injury-induced cold allodynia, which suggest that both of the investigated phenomena may be mediated by a similar mechanism, e.g. receptor desensitization. Moreover, the antisense oligonucleotides targeting beta-arrestin may constitute a new approach to the therapy of neuropathic pain.

Cortistatin and somatostatin mRNAs are differentially regulated in response to kainate

Cortistatin (CST) is a presumptive neuropeptide that shares 11 of its 14 amino acids with somatostatin (SST). CST and SST are expressed in partially overlapping but distinct populations of cortical interneurons. In the hippocampal formation, most CST-positive cells are also positive for SST. In contrast to SST, administration of CST into the rat brain ventricles reduces locomotor activity and specifically enhances slow wave sleep. Intracerebroventricular injection of CST or SST has been shown to protect against the neurotoxic effects of kainic acid. Here, we show that CST and SST mRNAs respond differently to kainate-induced seizures. Furthermore, comparison of the upstream sequences from the CST and SST precursor genes reveal that they contain binding motifs for different transcriptional regulatory factors. Our data demonstrate that CST and SST, which are often co-expressed in the same neurons, are regulated by different stimuli.

The effect of drugs of abuse on NMDAR1 receptor expression in the rat limbic system

An increasing body of evidence points to the role of N-methyl-D-aspartate (NMDA) receptors in the limbic system in the mechanism of drug dependence. We studied the influence of acute and repeated morphine (20 mg/kg i.p. or increasing dose for 10 days) and cocaine (3x20 mg/kg i.p. per day at hourly intervals, for 1 or 5 days) administration on the expression of glutamate NMDA receptor subunit 1 (NMDAR1) in the central and basolateral nuclei of the rat amygdala and hippocampal formation. Acute or chronic morphine and cocaine administration increased NMDAR1 mRNA level in the central and basolateral nuclei of the amygdala; morphine did so 3 h after the last dose and 48 h after withdrawal, cocaine 3 h after acute and last chronic dose. Morphine did not change the NMDAR1 mRNA level in the hippocampal formation, but chronic cocaine did decrease it in the dentate gyrus only. Our study suggests a possible link between the expression of NMDAR1 and changes in limbic system neuronal activity and behaviour after administration of morphine and cocaine. In summary, the present study demonstrated that morphine and cocaine influenced the expression of NMDAR1 in the structure of the limbic system which could be involved in dependence phenomena.