Involvement of GABAergic Systems in Manifestation of Pharmacological Activity of Desipramine

Abstract

ABSTRACT-We have conducted this study to elucidate the influence of GABAergic systems on manifestation of pharmacological activity of desipramine using both pharmacological and electrophysiological methods. Desipramine (20 mg /kg, i.p.) significantly blocked the adjuvant-induced thermal hyperalgesia, which was facilitated by treatment with the GABAA antagonist picrotoxin (2 mg/ kg, i.p.) or the GABAB antagonist saclofen (2 mg/kg, i.p.). This analgesic effect of desipramine was antagonized by post-treatment with picrotoxin or saclofen. However, none of these compounds showed any effect in normal animals without adjuvant-induced inflammation. In a slice preparation of the hippocampus, treatment with GABA (10 -5 -5´10 -4 M), baclofen (10 -5 -10 -4 M) or muscimol (10 -5 -10 -4 M) inhibited the field potential evoked in pyramidal neurons by Schaffer collateral stimulation. The inhibitory effect of GABA was facilitated by concurrent application of desipramine, carbamazepine or diazepam at a concentration of 5´10-5 -2´10 -4 M. The rank of order of facilitation is: desipramine > carbamazepine > diazepam. Desipramine also enhanced the inhibitory effect of baclofen and muscimol. These results suggest that desipramine causes GABAergic systems to activate still more, and this phenomenon appears to be involved in manifestation of the pharmacological activity of desipramine such as antinociception.

The antinociceptive effect of artemisinin on the inflammatory pain and role of GABAergic and opioidergic systems

“…1). The doses of the drugs used were chosen based on the literature review and preliminary pilot study [23,24].…”

DESIPRAMINE‐INDUCED Ca2+‐INDEPENDENT APOPTOSIS IN MG63 HUMAN OSTEOSARCOMA CELLS: DEPENDENCE ON P38 MITOGEN‐ACTIVATED PROTEIN KINASE‐REGULATED ACTIVATION OF CASPASE 3

“…Desipramine has been shown to alter levels of many molecules in vivo and in vitro. Desipramine decreases tumour necrosis factor- production in the brain, 1 downregulates the cortical  1 -and  2adrenoceptors in rat brain, 2 inhibits cytochrome P450 enzymes, 3 inhibits the neuronal and skeletal ATP-Ca 2 pump of the endoplasmic reticulum, 4 inhibits the plasma membrane Ca 2 pump, 5 enhances the function of membrane steroid transporters, 6 activates GABAergic systems 7 and alters protein kinase C activity in rat brain and rabbit platelets. 8 The aim of the present study was to explore the effect of desipramine on apoptotic pathways in osteosarcoma cells.…”

In vitro inhibition of recombinant ligand-gated ion channels by high concentrations of milnacipran

“…NMDA-activated ion current has also been shown to be inhibited by desipramine, imipramine and amitriptyline (White et al 1990;Watanabe et al 1993), although another study reported that desmethylimipramine potentiates NMDA responses (Lancaster and Davies 1991). The anti-nociceptive action of desipramine has been suggested to be mediated through the GABAergic system (Asahi and Yonehara 2001). Furthermore, TCAs have been shown to induce convulsive seizures which are due to inhibition of GABA A receptors (Malatynska et al 1988).…”