The Role of Glutamate in the Locus Coeruleus during Opioid Withdrawal and Effects of H-7, a Protein Kinase Inhibitor, on the Action of Glutamate in Rats

Abstract

To investigate the role of glutamate in the locus coeruleus (LC) during opioid withdrawal, rats were continuously infused with morphine (a µ-opioid receptor agonist, 26 nmol/µl/h) or butorphanol (a µ/δ/κ-mixed opioid receptor agonist, 26 nmol/µl/h) intracerebroventricularly (i.c.v.) via osmotic minipumps for 3 days. A direct LC injection of glutamate (1 or 10 nmol/5 µl) or naloxone (an opioid receptor antagonist, 24 nmol/5 µl) induced withdrawal signs in morphine- or butorphanol-dependent animals. However, these agents failed to precipitate any withdrawal signs in saline-treated control animals. On the other hand, the expression of withdrawal signs precipitated by the administration of glutamate or naloxone in opioid-dependent animals was completely blocked by concomitant infusion with 1 or 10 nmol/µl/h of an inhibitor of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine]. In animals that had been infused with opioids in the same manner, i.c.v. injection of naloxone (48 nmol/5 µl) precipitated withdrawal signs and increased extracellular fluid levels of glutamate in the LC of morphine- or butorphanol-dependent rats measured by in vivo microdialysis method. However, concomitant infusion with H-7 inhibited the increases of glutamate levels in the LC. These results strongly suggest that an expeditious release of glutamate in the LC region plays an important role in the expression of physical dependence on opioids. Furthermore, the action on glutamate release might be increased by the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity.

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence

“…Glutamate appears to increase, and glutamate antagonism appears to decrease, opioid withdrawal severity. For instance, increasing glutamate levels by directly injecting glutamate into the locus coeruleus (Tokuyama et al, 1998) or through pretreatment with the glutamate transporter inhibitor DL-TBOA, increases stretching, wet dog shakes, and teeth chattering (Sekiya et al, 2004). Decreasing glutamate levels through administration of the b-lactam antibiotic ceftriaxone (which upregulates the glutamate transporter) decreased jumping and teeth chattering in rats (Medrano et al, 2015), and increasing glutamate by coadministering dihydrokainic acid to block ceftriaxone increased withdrawal symptoms again (Medrano et al, 2015).…”

Glutamatergic substrates of drug addiction and alcoholism

“…• NMDA receptors antagonists [270,305,[319][320][321][322][323][324][325][326][327][328][329] • AMPA/KA receptor antagonists [322,330] • genetic deletion of NR2A [331] • genetic deletion of GluR1 [332] • mGluR5 antagonists [326,333,334] • stimulation of presynaptic Group II mGluRs [335][336][337][338] • administration of a glutamate release inhibitor [339] • activation of glutamate transporters [340] • inhibition of the processing of the putative glutamate precursor peptide N-acetylaspartylglutamate [341,342] On the contrary, facilitation of glutamatergic transmission, such as by administration of the glutamate transport inhibitor TBOA [343] or mGluR2/3 antagonists [344], actually exacerbates somatic signs of opiate withdrawal. There is a general consensus that the behavioral signs of opioid withdrawal are largely mediated by increased glutamatergic drive to the locus coeruleus [336,[344][345][346][347][348][349][350], an area that provides noradrenergic innervation to much of the brain. Reductions in glutamate transmission in this region reduce the expression of morphine withdrawal symptoms [348][349]…”

Decreases in Endogenous Opioid Peptides in the Rat Medullo-Coerulear Pathway after Chronic Morphine Treatment

“…Upregulation of cAMP in LC neurons may account for elevated basal firing rates (Kogan et al, 1992). In addition, the brainstem circuit linking the nucleus paragigantocellularis (PGi) and the LC has been implicated in contributing to the hyperactivity of LC neurons during opiate withdrawal because of increased glutamatergic transmission in this pathway (Rasmussen and Aghajanian, 1989;Akaoka and Aston-Jones, 1991;Tokuyama et al, 1998) during opiate withdrawal. Changes in neurochemical expression in afferent projections to the LC may be equally important in modulating noradrenergic neurons during chronic opiate exposure.…”