[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence suggest that extracellular ATP plays a role in pain signaling through the activation of ionotropic P2X-receptors, especially homomeric P2X3- and heteromeric P2X2/3-receptors on capsaicin-sensitive and -insensitive primary afferent neurons, respectively, at peripheral and spinal sites. We investigated the mechanisms of the induction and maintenance of mechanical allodynia produced by a single intrathecal (i.t.) administration of ATP in rats. We found that i.t. administration of ATP and the P2X-receptor agonist alpha,beta-methylene-ATP produced tactile allodynia which lasted more than 1 week. The i.t. ATP- and alpha,beta-methylene-ATP-produced long-lasting allodynia remained in neonatal capsaicin-treated adult rats. I.t. administration of a P2X3/P2X2/3-receptor selective antagonist completely prevented the induction (co-administration on day 0) and partially attenuated the early phase (day 1 post-ATP administration), but not the late phase (day 7 post-ATP administration) of maintenance of allodynia. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely prevented the induction phase, but not the early and late phases of maintenance of allodynia. Immunohistochemical and immunoblotting studies for microglial and astrocytic markers revealed that i.t. ATP administration caused spinal microglial activation within 1 day, and astrocytic activation which peaked at 1-3 days after ATP administration. Furthermore, minocycline, a microglial inhibitor, attenuated the induction but not the early and late phases of maintenance, while fluorocitrate, a glial metabolic inhibitor, attenuated the induction and the early phase but not the late phase of maintenance. Taken together, these results suggest that the activation of P2X-receptors, most likely spinal P2X2/3-receptors on capsaicin-insensitive primary afferent neurons, triggers the induction of long-lasting allodynia through NMDA receptors, and the induction and early maintenance phase, but not the late phase, is mediated through the functions of spinal glial cells.
[Show abstract][Hide abstract] ABSTRACT: Several studies indicate that the mu-opioid receptor plays a role in addiction not only to opiate drugs but also to alcohol and non-opiate addictive drugs. Our studies aim to reveal the associations between gene polymorphisms and methamphetamine (MAP) dependence/psychosis. We newly identified several polymorphisms and four substantial linkage disequilibrium (LD) blocks in the mu-opioid receptor (OPRM1) gene. We found significant differences in both genotype and allele frequencies of the single-nucleotide polymorphism (SNP) IVS2+G691C between control (n=232) and MAP-dependent/psychotic patients (n=128). There was also a significant association between IVS2+G691C and patients with transient psychosis. These results suggest that the OPRM1 gene variations may be a factor in development and prognosis of MAP psychosis.
The Pharmacogenomics Journal 01/2006; 6(3):179-88. · 5.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST) are key structures of the extended amygdala, which is suggested to be involved in drug addiction and reward. We have previously reported that the Ce plays a crucial role in the negative affective component of morphine withdrawal. In the present study, we examined the involvement of the neural pathway between the Ce and the BST in the negative affective component of morphine withdrawal in rats. Rats were rendered morphine dependent by s.c. implantation of a 75-mg morphine pellet for 3 days, and morphine withdrawal was precipitated by an i.p. injection of naloxone (0.3 mg/kg). In the place-conditioning paradigm, discrete bilateral excitotoxic lesions of the Ce or the BST significantly reduced naloxone-precipitated morphine withdrawal-induced conditioned place aversion. On the other hand, they had little effect on morphine withdrawal-induced somatic signs. In an immunohistochemical study for c-Fos protein, naloxone-precipitated morphine withdrawal dramatically induced c-Fos-immunoreactive neurons in the capsular part of the Ce, and the lateral and medial divisions of the BST. Bilateral excitotoxic lesion of the Ce reduced the number of morphine withdrawal-induced c-Fos-immunoreactive neurons in the lateral and medial BST, with significant decreases in the posterior, ventral and juxtacapsular parts of lateral division, and anterior part of the medial division, but not in the ventral part of the medial division of the BST. On the other hand, bilateral excitotoxic lesion of the BST had no effect on such c-Fos induction within the capsular part, nor the ventral and medial divisions of the Ce. These results suggest that activation of the BST mediated through the neural pathway from the Ce contributes to the negative affective component of morphine withdrawal.