Morphine-Induced Delay of Normal Cell Death in the Avian Ciliary Ganglion

Abstract

Repeated administration of morphine in increasing doses delayed normal cell death in the ciliary ganglion of the chick embryo; the effect was completely blocked by naloxone. Survival of spinal motoneurons was not affected. Morphine also inhibited potassium-stimulated synthesis of acetylcholine in ganglion cells cultured with muscle, suggesting that morphine can influence neurotransmission. Morphine's effect on cell death may be due to an inhibition of transmission at the neuromuscular junction, but opiates may also directly affect cell death. Although it is now known whether the endogenous opiates in the ciliary ganglion influence neuronal survival during embryogenesis, exogenous opiates can affect normal cell death in the autonomic nervous system.

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

“…Alternatively, the increases in tumour size could simply have been due to a direct effect of morphine that resulted in enhanced cellular proliferation in the tumours or reduced cell death. Indeed, morphine has been shown to prevent the normal cell death in the ciliary ganglion of the chick embryo, suggesting that in addition to modulating neurotransmission, it and other endogenous opiates may also regulate neurophysiology (22). The concentration of morphine appeared to be important in which effect it caused, as apoptosis in the chick embryo was only disrupted when used at the higher doses, whilst no effect was seen at the lower doses (6).…”

Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

“…Interestingly, current evidence indicates that depending on the cell type and opioid dosage, opioids can have paradoxicalneuroprotective or neurodegenerative effects (30,59,60). Morphine or Met-enkephalin can inhibit neuronal cell death in the avian ciliary ganglion (59,60). In a cell line transfected with μ opioid receptors, the μ agonist DAMGO ([D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin) activates Akt-induced neuroprotection (70).…”

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

“…Nearly 20 years ago, Meriney et al (1985) reported that morphine administered during embryogenesis prevents apoptosis of ciliary ganglion neurons that normally die during the period of synapse formation. They suggested that this effect was mediated through a neurotrophic mechanism or inhibition of neurotransmission (Meriney et al, 1985).…”

“…They suggested that this effect was mediated through a neurotrophic mechanism or inhibition of neurotransmission (Meriney et al, 1985). Morphine also prevented peroxynitrite-induced apoptosis in primary astrocytes (Kim et al, 2001) and enhanced the proliferation of endothelial cells (Gupta et al, 2002), kidney fibroblasts (Singhal et al, 1998), and adult hippocampal progenitor neurons (Persson et al, 2003).…”

“…Hence, G␤␥-mediated PI3K-dependent signaling pathways may contribute to the anti-apoptotic effects of morphine and selective agonists. These effects depend on opioid receptor stimulation and coupling to G i because the anti-apoptotic or protective effects of morphine are abolished with the opioid receptor antagonist naloxone (Meriney et al, 1985(Meriney et al, , 1991 with pertussis toxin (PTX), which inhibits G i , and with inhibitors of 1 Abbreviations: PKA, protein kinase A; CaM, calmodulin; CaMK, calmodulin kinase; DAMGO, [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin; DOR, ␦-opioid receptor; EGF, epidermal growth factor; EGFR, EGF receptor; Erk, extracellular-regulated kinase; G␣, GTP-binding protein, ␣ subunit; G␤␥, GTP-binding protein, ␤ and ␥ subunit; GDP, G-protein dissociation protein; G i , inhibitory pertussis toxin-sensitive G-protein; GPCR, G-protein-coupled receptor; GRK, G-proteincoupled receptor kinase; G z , inhibitory pertussis toxin-insensitive G-protein; HIV, human immunodeficiency virus; ICAM, intercellular cell adhesion molecule; IL, interleukin; JNK, c-Jun-N-terminal kinase; KOR, -opioid receptor; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MKK, mitogen-activated protein kinase kinase; MMP, metalloproteinase; MOR, -opioid receptor; NF-B, nuclear factor kappa B; NK cell, natural killer cell; NMDA-R, N-methyl-D-aspartate receptor; NO, nitric oxide; NOS, nitric-oxide synthase; PAR, proteinase-activated receptor; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A (cAMP-dependent protein kinase); PKB/Akt, protein kinase B; PKC, protein kinase C; PTX, pertussis toxin; RGS, regulator of G-protein signaling; Src, non-receptor tyrosine kinase; TGF, tissue growth factor; TNF␣, tumor necrosis factor ␣; U50,488H, trans-(Ϯ)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzene acetamide methane-sulfonate hydrate; VEGF, vascular endothelial growth factor. Grimm et al, 1998a; OPIOIDS AS MODULATORS OF CELL DEATH AND SURVIVAL Nicotine Minna, 1990, 1994 Lung cancer tissue specimens OPIOIDS AS MODULATORS OF CELL DEATH AND SURVIVAL Belcheva et al, 2001 ConA, concanavalin A; LPS, lipopolysaccharide; Nx, naloxone; Ntx, naltrexone; CCI, chronic constriction injury; ICE, interleukin-converting enzyme; CHO, chinese hamster ovary; iNOS, inducible NOS; eNOS, endothelial NOS; DADLE, [D-Ala PI3K such as wortmannin and LY294002 (Polakiewicz et al, 1998b;Kim et al, 2001).…”