Chronic morphine induces up‐regulation of the pro‐apoptotic Fas receptor and down‐regulation of the anti‐apoptotic Bcl‐2 oncoprotein in rat brain

Abstract

1 This study was designed to assess the in¯uence of activation and blockade of the endogenous opioid system in the brain on two key proteins involved in the regulation of programmed cell death: the pro-apoptotic Fas receptor and the anti-apoptotic Bcl-2 oncoprotein. 2 The acute treatment of rats with the m-opioid receptor agonist morphine (3 ± 30 mg kg 71 , i.p., 2 h) did not modify the immunodensity of Fas or Bcl-2 proteins in the cerebral cortex. Similarly, the acute treatment with low and high doses of the antagonist naloxone (1 and 100 mg kg 71 , i.p., 2 h) did not alter Fas or Bcl-2 protein expression in brain cortex. These results discounted a tonic regulation through opioid receptors on Fas and Bcl-2 proteins in rat brain.

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

“…and Rao, 2000) or, conversely, to deliver survival signals (eg neurite growth, Desbarats et al, 2003). In previous studies in rats (Boronat et al, 2001;García-Fuster et al, 2003a, 2004a, heroin/morphine addiction and opiate withdrawal were associated with upregulation of Fas in the brain (ie, increased content of native receptor and complexes of monomers relevant in Fas signaling). In the current study, FADD, the adaptor protein that couples Fas to caspase-8 and transmits the death signal, followed an opposite modulation.…”

“…For the chronic treatment with morphine, the rats were injected i.p. three times daily during 5 days with increasing doses of the opiate (10-100 mg/kg) (Boronat et al, 2001) and killed 2 h after the last dose. After this chronic treatment, naloxone (2 mg/kg, i.p., 2 h)-precipitated withdrawal or spontaneous (24 and 48 h) opiate withdrawal was induced, which resulted in the standard behavioral reaction (data not shown; see Gabilondo and García-Sevilla, 1995;Miralles et al, 2005).…”

“…The amount of target proteins in brain samples of rats treated with opiate drugs was compared in the same gel with that of control rats which received saline or DMSO solution. Experiments were performed by using protein samples known to be within the linear range for immunolabeling of FADD and other target proteins (see Boronat et al, 2001). The quantification procedure was assessed 3-5 times in different gels (each gel with different brain samples from saline/DMSO-and drugtreated rats).…”

“…In this context, Fas proteins (native and glycosylated receptor, and complexes of monomers relevant in Fas signaling) were shown to be upregulated after chronic heroin and morphine treatments and heroin withdrawal in rat brain (Boronat et al, 2001;García-Fuster et al, 2003a, 2004a, which suggested a role for Fas in opiate addiction either as promoter of abnormal cell death (see Yin et al, 1999;Wang et al, 2002) or as a possible nonapoptotic signal transducer of opioid receptors (see Tegeder and Geisslinger, 2004). To clarify this issue, the present study was designed to assess the modulation of FADD (the transmitter of Fas signal) and effector caspase-8/3 in the brain after the acute and chronic treatments with selective m-, d-, and k-opioid peptide (MOP-, DOP-, and KOP-) receptor agonists, and during the induction of opiate withdrawal in rats.…”

Role of Multifunctional FADD (Fas-Associated Death Domain) Adaptor in Drug Addiction

“…In fact, morphine was reported to increase, through a naloxone-sensitive mechanism, the expression of Fas receptor mRNA in mouse splenocytes and in human blood lymphocytes (Yin et al, 1999). However, the possibility of opiate-induced cell death in the mature brain, including the brains of human addicts, still is a debated issue (Boronat et al, 2001;Tegeder and Geisslinger, 2004;Liao et al, 2005;CunhaOliveira et al, 2008;García-Fuster et al, 2008b;Tramullas et al, 2008;Zhang et al, 2008). Fig.…”