Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

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

“…In the current study, FADD, the adaptor protein that couples Fas to caspase-8 and transmits the death signal, followed an opposite modulation. Together, the results suggest that possible apoptotic signals engaged by Fas activation (see Tegeder and Geisslinger, 2004;Liao et al, 2005) would be offset by decreased signal transduction through FADD and effector caspases-8/3 (not altered by any opiate treatment). Since the activation of ERK1/2 is crucial for various antiapoptotic mechanisms (Wada and Penninger, 2004), including protection against Fas-mediated apoptosis (Holmström et al, 1999(Holmström et al, , 2000, it is tempting to conclude that opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of ERK1/2 signaling.…”

“…The reduction of FADD content induced by opiate drugs may be related to the recently uncovered neuroprotective or survival-promoting effects associated with extra-analgesic doses of opiates (acute effects) in various systems (Tegeder and Geisslinger, 2004) Representative immunoblots of (a) human 55 kDa procaspase-8 and Ep20 kDa cleavage form (arrows), (b) human 32 kDa procaspase-3 (arrow), and (c) rat 32 kDa pro-caspase-3 and Ep20 kDa cleavage form (arrows; PC: positive control), as well as the corresponding for b-actin (loading control) protein immunoreactivities in the cerebral cortex of control and morphine-dependent rats (samples: 40 mg protein). Effects of chronic saline (C), chronic morphine (M, 10-100 mg/kg for 5 days), and chronic morphine followed by naloxone (Nlx, 2 mg/kg, i.p.…”

“…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.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Apart from peripheral sensory neurons, opioid peptides and opioid receptors are expressed in immune cells (see II.4), fibroblasts, melanocytes, and keratinocytes (Tegeder and Geisslinger, 2004;Sharp, 2006;Chen et al, 2008; for review, see Bigliardi et al, 2009;Busch-Dienstfertig and Stein, 2010).…”

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

“…Therefore, FADD is instrumental in controlling a variety of intracellular processes that regulate cell growth/survival/ apoptosis in a complex dance of changing partners and overlapping steps. Indeed, other drugs of abuse (ie opiates) have recently been shown to promote either survival or proliferating neural signals (Tegeder and Geisslinger, 2004;Barry and Zuo, 2005) perhaps through inhibition of FADD by a mechanism dependent on the activation of the antiapoptotic ERK1/2 signaling pathway (Garcia-Fuster et al, 2007).…”