Non-Analgesic Effects of Opioids: Neuroprotection in the Retina

Home , Bremazocine, Spiradoline

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/228099262

Article in Current pharmaceutical design · June 2012 DOI: 10.2174/138161212803582441 · Source: PubMed

CITATIONS READS 17 111

3 authors:

Shahid Husain Yasir Abdul Medical University of South Carolina Augusta University

52 PUBLICATIONS 889 CITATIONS 8 PUBLICATIONS 85 CITATIONS

SEE PROFILE SEE PROFILE

David E Potter Texas A&M University System Health Science C…

139 PUBLICATIONS 2,156 CITATIONS

SEE PROFILE

All content following this page was uploaded by Shahid Husain on 01 June 2014.

The user has requested enhancement of the downloaded file. Send Orders of Reprints at [email protected] Current Pharmaceutical Design, 2012, 18, 5919-5926 5919

Non-Analgesic Effects of Opioids: Neuroprotection in the Retina

Shahid Husain*, Yasir Abdul, and David E. Potter

Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, SC 29425, USA

Abstract: Inadequate blood flow in the retina (ischemia) is a common cause of visual impairment and blindness. Retinal ischemia plays a pivotal role in a number of ocular degenerative diseases such as diabetic retinopathy, glaucoma, and retinal artery occlusion. The se- quence of events by which ischemia leads to retinal degeneration are not completely understood, but likely involve both necrotic and apoptotic processes. A variety of diverse chemical mediators (e.g., glutamate, oxygen free-radical, nitric oxide, and proinflammatory cytokines) have been implicated as participants in ischemic retinal injury. In the eye, experimental and/or clinical evidence has suggested roles for endogenous opioids and their receptors in the regulation of iris function, aqueous humor dynamics, corneal wound healing, and retinal development and neuroprotection. In numerous vital organs, opioid receptor activation prior to ischemia or severe hypoxia is neuroprotective. Recently, activation of opioid-receptors, particularly -opioid-receptors (DOR), has been demonstrated to suppress several steps in the deleterious cascade of events during ischemic/hypoxic stress. In providing neuroprotection against ischemia, opioid-receptor activation appears to block proinflammatory cytokines, such as TNF-, and glutamate excitotoxicity. Depending on duration and severity of cellular stress, DOR activation can trigger different mechanisms at multiple levels to preserve neuronal survival, including: stabilized ionic homeostasis, augmented pro-survival signaling (e.g., PKC, ERK, PI3K/Akt) and enhanced anti-oxidative capacity. This review will summarize the potential roles of opioids in protecting the viability of ocular tissues. Special emphasis will be focused on enhancing the understanding of the molecular mechanisms of opioid actions in protecting the retina against ischemic/hypoxic injury. Keywords: Opioid, retina, ischemia, TNF-, opioid-receptor.

INTRODUCTION tered in glaucoma. In this regard, it is of interest that the reported Clinically, opioids are not only powerful analgesics, but they density of opioid binding sites in the rat retina is comparable to that are modulators/mediators in: stress responses; immune, cardiovas- of the rat brain. Recently, this laboratory has demonstrated the neu- cular, gastrointestinal and neural systems; and cell survival. The roprotective activity of opioids in the retina against an ischemic diverse biological effects of opioids, including cytoprotection, anal- insult in laboratory animals [5]. Furthermore, we have shown that gesia, neuroendocrine regulation, immunomodulation, and behav- opioid-receptor activation attenuates ischemia-induced TNF- pro- ioral modification, are manifested through specific opioid receptors duction [6]. Thus, it is proposed that opioidergic ligands could that are distributed throughout the body. Thus, in addition to being serve as leads for the discovery of novel drugs for therapy of ocular effective analgesics, opioids can produce a myriad of pharmacol- diseases particularly those characterized by dysfunction of neuro- ogical actions that might have application in a variety of diseases, logical and/or immunological components. including ocular disorders. Under the influence of cognitive and NON-ANALGESIC EFFECTS OF OPIOIDS: NEUROPRO- non-cognitive stimuli, activation of opioid receptors occurs by re- TECTION lease of endogenous peptides (e.g., endorphins, dynorphins, and enkephalins) [1]. To date the opioid receptors that have been cloned In numerous systems, opioid receptor activation has been are: -opioid (OP1), -opioid (OP2), and μ-opioid (OP3) receptors. shown to elicit a protective effect during situations of stress pro- Based upon pharmacological evidence -, -, and μ-opioid recep- duced by hypoxia, ischemia, cold, or an acidic environment [7-10]. tors are further sub-classified into 1, 2; 1, 2, 3; and μ1, μ2 and For example, an increased production and release of opioid peptides μ3-opioid receptors. The expression of opioid receptors have been has been proposed as a part of the endogenous protective response shown in virtually all major organ systems including the central to ischemia-reperfusion injury in heart and brain [11]. Furthermore, nervous system [2], heart [3], and eye [4, 5]. The opioid receptors, treatment with either a non-selective agonist (morphine) or rela- upon binding exogenous or endogenous ligands, regulate a multi- tively selective agonists (-opioid [BRL-52537], or -opioid [BW- tude of intracellular signaling pathways. Numerous studies have 373U86]) resulted in a significant reduction in infarct size in the shown that multitudes of signaling pathways are regulated by three heart following reperfusion [12]. Studies have shown that the glu- classes of seven transmembrane opioid receptors, through a variety tamate- and hypoxia-induced neuronal death of rat neocortical neu- of heterotrimeric G-protein-coupled receptors (GPCRs). rons was reduced when opioids were present during the insult [13]. Morphine administration during embryogenesis prevents apoptosis Endogenous opioid peptides are biologically relevant ligands in of ciliary ganglion neurons that normally die during the period of virtually all major organs where they facilitate signaling among synapse formation [14]. Moreover, morphine administration has immune, endocrine, and nervous inputs. This review will provide been shown to reduce naturally occurring neuronal death [14]. Oth- an overview of the complexity of opioid receptor-mediated neuro- ers have proposed that endogenous opioid peptides act as trophic protection in the eye and compare it to reports of similar effects in factors thereby regulating neuronal survival and cell proliferation non-ocular systems. Based on existing literature and current data, during nervous system development [15, 16]. In addition, activation evidence suggests that opioidergic ligands have the potential to of opioid receptors by endogenous/exogenous opioid agonists be- protect the retina against damaging influences, particularly those fore an ischemic insult provides protection in a variety of organs. that are associated with ischemic conditions such as those encoun This phenomenon is called opioid preconditioning and has been

shown in the heart [17], brain [18], and eye [5]. Moreover, some *Address correspondence to this author at the Storm Eye Institute, Room investigators have proposed that endogenous opioids should be 511, Medical University of South Carolina, 167 Ashley Ave, Charleston, SC considered as key messenger molecules (cytokines) that orchestrate 29425, USA, Tel: 843-792-2792; Fax: 843-792-1723; E-mail: [email protected]

1381-6128/12 $58.00+.00 © 2012 Bentham Science Publishers 5920 Current Pharmaceutical Design, 2012, Vol. 18, No. 37 Husain et al. cellular activity at the crossroads of the inflammatory/immune re- Opioid receptor ligands are known to alter IOP in humans [43, sponses [19]. 44, 47, 48]. Originally, morphine was thought to raise intraocular It is of interest that endogenous opioid peptides regulate many pressure; subsequently, it was demonstrated to lower intraocular physiological functions including neural, endocrine and immune pressure. Interestingly, the intraocular pressure of opium and heroin responses [20-22] as well as energy conserving/protective responses addicts has been demonstrated to be lower than that of non-addicted that occur during hibernation [23]. Synthetic opioids will mimic the patients [49]. Moreover, conjunctival instillation of opioid antago- cytoprotective effects of endogenous opioidergic ligands released nist, naloxone, increases intraocular pressure (IOP) in morphine- during hibernation, and the effects are initiated by -, -, and μ- addicted patients, and this phenomenon has been proposed as a opioidergic ligands. During hibernation, blood flow to the brain is possible test for detecting misuse of morphine [47, 49]. In the eye, severely reduced, but central neurons remain viable [24] and car- opioid agonists have been demonstrated to lower IOP and enhance diorespiratory function is still regulated during torpor [25]. Hiber- outflow facility in both human and animals [43, 50]. Additionally, nation-induced neuroprotection is not simply due to colder brain relatively selective - and -opioid-receptor agonists such as temperatures, but appears to be due to increased resistance to DPDPE, bremazocine, spiradoline and dynorphin have been shown ischemic conditions [25]. In active, summer ground squirrels, intra- to reduce IOP via reducing aqueous flow rates in New Zealand venous infusion of DADLE (a -opioid receptor agonist) will in- rabbits [50-53]. Kappa-opioid agonists also have other neuroendo- duce hibernation [26]. Similarly, injections of deltorphin (-opioid crine effects, such as the release of atrial natriuretic peptide (ANP), receptor agonist) as well as hibernating woodchuck plasma injected which has been associated with enhanced outflow facility in rabbits into mice induced neuroprotection prior to induction of focal [54]. Moreover, activation of the endogenous opioidergic system by ischemia [27]. This natural form of neuroprotection is hypothesized electroacupuncture which elevates levels of endomorphin-1, beta- to be due, in part, to enhanced -opioid receptor activation by endorphin and encephalin has been demonstrated to induce ocular endogenously produced ligands. hypotension in rabbits [55]. There have also been claims of im- proved visual acuity and reduced IOP have been reported in re- Early studies demonstrated that circulating levels of endoge- sponse to acupuncture in glaucomatous patients [56]. These clinical nous opioid-peptides increase during periods of generalized stress and basic research findings suggest that opioid receptors can have a [28]. Furthermore, more specific stress in the form of myocardial modulatory role on aqueous humor dynamics and possibly influ- ischemia has been shown to induce synthesis and release of opioid ence the decline of visual field defects in glaucoma. However, the peptides that subsequently activate opioid receptors and provide potential utility of the opioidergic system in the protection against protection to the myocardium [11, 29]. There is a growing body of ischemic injury in the retina remains to be established. evidence from studies of the heart and brain supporting the idea that activation of the opioid system plays a central role in neuroprotec- Recently, we have identified the expression and location of the tion, and that the non-selective opioid antagonist, naloxone, can three, opioid-receptor sub-types (, , and μ) in the adult rat retina, prevent neuroprotection in these tissues [7, 30-32]. In nervous tis- and demonstrated that opioid-receptor activation is required for the sue, -opioid-receptor agonists were shown to modulate glutamate development of ischemic preconditioning in the rat model [5]. Con- excitotoxicity by inhibiting presynaptic glutamate excitotoxicity by trol animals subjected only to 45 minutes retinal ischemia showed a inhibiting presynaptic glutamate release in vitro [33], via closure of significant reduction in ERG a- and b-wave measurements. Mor- N-type Ca2+ channels and restriction of Ca2+ entry into presynaptic phometric analysis of these eyes revealed an overall reduction in terminals [34]. Delta-opioid receptors (DOR) have been shown to retinal thickness, which was primarily due to thinning of the inner be involved in neuroprotection against hypoxic/ischemic insults in plexiform, and inner nuclear layers. However, mild disorganization various models, including in vitro when individual neurons and and thinning of the outer nuclear layer was also observed. Animals brain slices are exposed to hypoxia or oxygen-glucose deprivation that received an ischemic preconditioning procedure for 5 minutes, as well as in vivo when the brain is subjected to cerebral ischemia 24 hours prior to ischemic injury were protected from the functional [35-41]. One study showed that selective -opioid-receptor agonist and structural changes induced by subsequent ischemic injury [5]. (DADLE) exhibited neuroprotective effects by decreasing release Pretreatment with the nonselective opioid-receptor antagonist, of glutamate [42]. Based on the published literature, it appears that naloxone, prior to ischemic preconditioning, suppressed the func- opioid-mediated neuroprotection is not tissue specific, and that tional and morphological protection induced by this preconditioning multiple pathways are involved. procedure [5]. Additionally, administration of the exogenous opioid agonist, morphine, protected the retina against ischemic injury. OPIOID RECEPTORS AND THEIR FUNCTIONS IN THE Ischemia-induced retinal damage was ameliorated in the morphine- EYE treated animals in a dose-dependent fashion (ED50 = 0.18 mg/kg), Although the expression patterns of endogenous opioid- as measured by preservation of the a- and b-wave amplitudes [5]. peptides and receptors have been studied extensively in tissues/cells These results with opioidergic drugs are similar to studies per- of other organ systems, the same level of attention has not been formed in the heart and brain, where naloxone administration has forthcoming in tissues/cells of the eye. However, opioid receptors also been shown to inhibit the protective effects of ischemic pre- have been demonstrated to be present in tissues of the anterior seg- conditioning against damage caused by hypoxia and ischemic in- ment as well as in various layers of the retina [4, 5]. Experimental jury [7, 32, 57]. Similar to results from this laboratory, Riazi- and/or clinical evidence has suggested potential roles for endoge- Esfahani and colleagues found that intravitreal administration of nous opioids and their receptors in the regulation of iris function, morphine to rabbits provides retina neuroprotection against accommodative power, aqueous humor dynamics, corneal wound ischemic injury [58]. The expression of opioid receptors within the healing, and retinal development. Various endogenous opioid pep- inner retinal layers is consistent with a neuroprotective role for tides, as well as their receptors, have been identified in the eyes of opioid receptors in the retina. humans [43], rabbits [44], and rats [5, 45]. Opioid-containing In summary, it is highly probable that retinal ischemia plays a (enkephalinergic) neurons have been reported to be present in the central role in several ocular diseases involving the posterior seg- iris-ciliary-body, choroid membranes, cornea, lacrimal glands and ment. Likewise, animal studies have provided evidence that both adnexa of various species [45, 46]. Although opioids have been endogenous and exogenous opioids initiate neuroprotective events demonstrated to alter a variety of ocular functions, the detailed in the ischemic retina [5, 58]. Therefore, it is important to empha- mechanisms by which opioidergic ligands elicit their pharmacol- size that our findings, and that of others support the concept that ogical actions in the eye have not been clearly defined. enhancement of opioidergic activity during critical periods of ocu- Ocular Neuroprotection by Opioids Current Pharmaceutical Design, 2012, Vol. 18, No. 37 5921 lar ischemia/hypoxia presents a viable neuroprotective strategy for sure (IOP), caused by raising the IOP above the systemic blood the treatment of retinal diseases. pressure, is frequently used as an animal model in retinal research, and has been described in numerous studies [5, 62-65]. This method ISCHEMIC INJURY: CASCADE OF EVENTS produces global ischemia by obstructing both the retinal and uveal Ischemic injury, induced by vascular occlusion, initiates a com- circulation, as evidenced by the reduction in amplitude of the ERG plex cascade of cellular events, encompassing many different path- wave-forms, and pallor in the fundus and iris. Retinal ischemia ways, that ultimately leads to irreversible tissue injury, i.e., infarc- followed by reperfusion shows a clear thinning of the inner part of tion. The extent and temporal evolution of ischemic injury is influ- the retina. Moreover, the pathological findings in the rat retina after enced by many factors that include the adequacy of collateral blood ischemia/reperfusion injury have a striking resemblance to that flow, temperature, glucose levels, and other metabolic factors. The found in the retina of the glaucomatous patient [66]. variability of these factors affects the time window available for Retinal ischemia plays a pivotal role in a number of retinal de- initiation of therapy that might ameliorate the size of the ultimate generative diseases such as diabetic retinopathy, glaucoma, and infarction among individual patients [59, 60]. The other potential retinal artery occlusion [62]. Studies have provided evidence that approach to acute ischemic treatment is to try to impede the tumor necrosis factor (TNF)- , plays a central role in the patho- ischemic cascade by targeting various components of the cascade genesis of a number of degenerative retinal diseases that have that are deemed to be of importance. This approach is called a neu- ischemic component [67-70]. roprotective strategy and has been used in numerous vital organs including the eye [5]. This approach is elaborated in the following OPIOIDERGIC REGULATION OF TNF- ACTIVITY IN section that examines the multiple sites and potential molecular THE RETINA mechanism (s) for opioid-mediated neuroprotection. That section Tumor necrosis factor- (TNF-) is known as a potent immu- also describes multiple targets for opioid action (see Fig. 1). During nomediator and proinflammatory cytokine that is up-regulated rap- ischemia, excessive amounts of neurotransmitters, especially exci- idly in the brain after injury [71]. TNF- exerts its biological func- tatory amino acids such as glutamate and aspartate, are released and tions by interaction with two membrane receptors: TNF receptor- cause an increase in the influx of sodium and calcium ions via post- type-1 (TNF-R1 or p55) and -2 (TNF-R2 or p75). TNF--induced synaptic glutamate receptor activation (see Fig. 1). Cortical injury is cell death is primarily mediated via TNF-R1 receptors [72], mediated mostly via NMDA receptors, whereas brainstem injury is whereas TNF-R2 receptors have been suggested to be involved in mainly AMPA receptor dependent [61]. Along with glutamatergic neuroprotection [73]. The activation of TNF-R1 leads to the activa- excitotoxicity and calcium influx, there is a free radical attack and tion of multiple apoptotic pathways involving the activation of the prolonged neuronal hyperactivity both of which causes further neu- pro-death Bcl-2 family of proteins, reactive oxygen species [74], ronal damage. Following the initial excitotoxicity injury and loss of and c-jun NH2-terminal kinase [75]. These pathways are closely synaptic connectivity, inflammation and apoptosis increases over interlinked and mainly act on mitochondrial function, resulting in hours to days, and neurotrophic factors are down-regulated, these apoptosis. events hinder the neuron’s ability to repair or regenerate, and eventually cause loss of neurons. Both TNF- mRNA and protein expression have been shown to be increased in the retina following ischemia [76, 77]. TNF- is RETINAL ISCHEMIA produced by reactivated astrocytes and microglia in addition to macrophages, lymphoid cells, mast cells, and endothelial cells [78]. Retinal ischemia, in its various guises, is a common clinical Recently, we have demonstrated that production of TNF- after entity and it remains a common cause of visual impairment and ischemia/reperfusion injury is an early event, which most likely blindness. Retinal ischemia, induced by elevated intraocular pres-

Ischemia

Mitochondrial dysfunction GSH-Px Glial Activation

ATP Deplet ion Nitric Oxide, Free DOR Radical, TNF-a

Na+ & K + influx Depolarization Caspases Survival Kinases (MAP Glut amat e Kinase, Release PI3/AKT, STAT Apoptosis

Ac ute & Chronic Glutamate Neuronal Injury Neuronal Cell Death Excitotoxicity

Fig. (1). Putative pathways for ischemia-induced retina degeneration and its preservation in the presence of opioids. 5922 Current Pharmaceutical Design, 2012, Vol. 18, No. 37 Husain et al. initiates and activates a downstream signaling cascade, leading to gene expression, and the up-regulation of stress proteins such as inner retina cell death under ischemic conditions. Furthermore, we heme-oxygenase, HSP-27, HSP-70 and HSP-90 [64, 108, 111]. have shown a co-localization of TNF- and GFAP immunostaining Recently, we have shown that opioid-receptor activation is required in the ischemic retina sections, suggesting that glial cells are the for the development of retinal ischemic preconditioning and exoge- primary source for the TNF- production in ischemic conditions nous activation of opioid-receptors also provides significant neuro- [6]. Cytotoxic effects of TNF- are largely associated with its abil- protection against acute ischemic injury [5]. Studies have provided ity to induce apoptosis-signaling via TNF-R1-receptor activation. evidence that hypoxic preconditioning in the retina can inhibit the The dramatic increase in TNF- production after ischemic and production of reactive oxygen species and up-regulate -opioid- excitotoxic brain injury suggests key roles for this cytokine in or- receptors [112]. However, elucidation of specific signaling path- chestrating the neurodegenerative process. Its excessive synthesis ways involved in opioid-mediated retina neuroprotection require after CNS trauma has been correlated with poor outcome following additional study. mechanical trauma [79]; while inhibition of excessive TNF- activ- Studies have shown that -opioid agonists can suppress LPS- ity is accompanied by reduced brain damage [80]. Additionally, induced p38 MAPK activation and expression of TNF- and MIP-2 TNF- is up-regulated in the glaucomatous optic nerve head and in murine macrophages [113]. Morphine treatment inhibits LPS- retina [69, 81, 82]. Growing evidence supports that TNF- through induced NF-B in human neutrophils and monocytes [114], and the binding of TNF-R1, a death receptor, is involved in mediating also results in the activation and phosphorylation of PI3/Akt in rats RGC death during ischemic and glaucomatous neurodegeneration. [115]. Additionally, studies have shown that p38 MAP kinase plays In addition, the expression of TNF- receptors on astrocytes and a key role in the glutamate-induced apoptosis of retinal ganglion axons of the glaucomatous optic nerve head, suggests that the TNF- cells [116] and an increased phosphorylation of p38 MAP kinase stimulates cytodestructive processes in both the astrocytes and and JNK has been noted in experimental glaucoma models [117]. axons in the optic nerve head [82]. NF-B regulates the production of many proinflammatory cytoki- In other systems, opioids have been shown to suppress the pro- nes (e.g., TNF- and interleukins). In the central nervous system, duction of proinflammatory cytokines. For example: 1) morphine NF-B is ubiquitously expressed in neurons and glia and can be attenuates peptidoglycan (PGN)-stimulated TNF- from monocytes activated by many stimuli, including an ischemic insult [118], oxi- via activation of μ-opioid receptor [83]; 2) -endorphin inhibited dative stress [119], and glutamate [120]. In the eye, a pivotal role interleukin-2 release from concanavalin-A-stimulated splenic lym- for NF-B in TNF--mediated optic nerve degeneration has been phocytes [84]; 3) endorphin and met-enkephalin inhibited TNF-, suggested [121]. However, it is not clear if these pathways (e.g., interleukin-1, and MMP-9 production at the level of mRNA ex- p38 MAP kinase, NF-B, and PI3K/Akt) in the retina can be regu- pression in patients with rheumatoid arthritis [85]; and 4) -opioid lated by opioids during ischemic injury. This area of ocular research agonist (U50,488) inhibited HIV-1 Tat-induced chemokines (MCP- requires further investigation. 1) in human brain astrocytes [86]. The phosphatidylinositol-3 kinase (PI3K)/Akt signaling path- In the eye, we have recently shown that ischemia-induced TNF- way plays a central role in regulating cell growth, proliferation, production in Brown Norway rats and lipopolysaccharide (LPD)- survival, and inflammatory responses under physiological and induced TNF- release from glial cells (e.g.; astrocytes and micro- pathophysiological conditions. The activation of the PI3K/Akt glia) are drastically attenuated by opioid-receptor activation [6]. pathway negatively modulates genes that promote vascular perme- Based on these findings and recently published data from this labo- ability and inflammation, and thereby protects vascular function ratory [6], it seems reasonable to speculate that opioidergic agonists [122]. Additionally, activation of Akt has been shown to be neuro- enhance retinal neuroprotection by inhibiting the production of protective via inhibition of apoptosis [123]. In the eye, studies have TNF- initiated by ischemic conditions. shown a potential participation of Akt in the development of ischemic preconditioning against an acute ischemic insult [124]. An POTENTIAL MOLECULAR MECHANISMS FOR OPIOID- essential role for the PI3/Akt signaling pathways in opioid- MEDIATED NEUROPROTECTION mediated neuroprotection has been previously demonstrated [105, Opioid receptors regulate cellular activity utilizing a diverse 125]. In addition, PI3K/Akt has been shown to play a central role in spectrum of signaling pathways including adenylyl cyclase (AC), the regulation of proinflammatory cytokine production, MAP phospholipase C (PLC), protein kinase C (PKC), PI3K, ion chan- kinase activation, and thus neuroprotective events. For example, nels, NF-B, PI3K/Akt, and mitogen-activated protein (MAP) activation of PI3K/Akt negatively regulates: 1) LPS-induced TNF- kinases. Activation of opioid receptors has been associated with production in human monocytes [126]; 2) flagellin-induced inter- inhibition of adenylyl cyclase [87-92], stimulation of potassium leukin (IL)-6, IL-8, and inducible nitric oxide [127]; 3) Nod2- channel conductance [93-96], inhibition of calcium conductance induced NF-B activation and IL-8 expression in HEK293T cells [97-99], activation of PI3K/Akt [89, 100], activation of NF-B [128]; and 4) JNK pathways in PC12 cells [129]. Based on these [101], activation of PLC [102], activation of PKC [103], and regu- published reports, it appears that PI3K/Akt pathways play an in- lation of mitogen-activated protein kinase signaling pathways [104- strumental role in opioid-mediated neuroprotection; however, their 106]. role in opioid-mediated retina neuroprotection against ischemic Although the molecular and cellular events involved in injury to the retina requires confirmation. ischemic retinal degeneration have been studied for several years, Due to the complex nature of opioid-receptor pharmacology at the identification of efficacious therapies still remains to be deter- multiple sites, the remaining discussion will focus primarily on the mined. To identify novel neuroprotective strategies for the retina, roles of -opioid-receptors (DOR) in the neuroprotection of non- we and others have investigated the cytoprotective mechanisms ocular and ocular tissues. DOR activation offers a unique form of induced by ischemic preconditioning (IPC) [5, 64]. Ischemic pre- neuroprotection because it appears to be a highly conserved, induc- conditioning or ischemic tolerance is defined as the ability of one or ible mechanism, which is used by vertebrate extremophiles (e.g., more brief non-injuring periods of ischemia to protect a tissue from mammalian hibernators and hypoxia-resistant vertebrates). Also, subsequent severe ischemic insults. The cytoprotective responses to DOR dependent protection is observed in various tissues other than ischemic preconditioning have been identified in heart, brain, liver, brain, which makes it an attractive candidate for providing systemic lung, skeletal muscle, spinal cord, and retina [8, 64, 107-110]. Stud- protection during whole-body ischemia/hypoxia. ies have provided evidence that in the retina, neuroprotection in- Fig. (1) shows the multiple pathways that are activated under duced by ischemic preconditioning may involve multiple mecha- ischemic conditions, and the possible sites of action for the opioid- nisms including adenosine-receptor activation, HIF-1-induced receptor agonist in promoting neuroprotection. It is presumed that Ocular Neuroprotection by Opioids Current Pharmaceutical Design, 2012, Vol. 18, No. 37 5923 counteractive actions of opioids are at multiple sites serve to pre- nistic features may be tissue-specific and species specific, it seems serve the neurons in general and the retinal ganglion cells in par- reasonable to assume that DOR agonists attenuate multiple delete- ticular. Under ischemic conditions in the eye, glial cells are acti- rious ischemic events at several membrane and intracellular sites. vated, which subsequently activates downstream signaling targets Studies have shown that DOR up-regulates the activity of such as stress-related MAP kinases (p38 MAP kinase and JNK). ERK1/2 and reduces the release of cytochrome C, thus protecting The stress-related kinases then modulate the activity and/or expres- neurons from hypoxic injury [38]. DOR activation attenuates oxida- sion of transcriptional factor, NF-B. Once NF-B is translocated tive injury in the brain exposed to ischemia/reperfusion by enhanc- to the nucleus, it induces the expression of target genes, such as ing the SOD and GSH-Px activities (see Fig. 1) and inhibiting inducible nitric oxide synthase (iNOS) and proinflammatory cyto- caspase activity [130]. kines like TNF-. Excessive production of TNF- initiates caspase activation resulting in retinal ganglion cell death by apoptosis. CONCLUSION However, it is presumed that opioid-receptor activation counterbal- Retinal ischemia plays a pivotal role in a number of retinal de- ances the detrimental actions by: 1) activating survival kinases such generative diseases such as diabetic retinopathy, glaucoma, and as ERK1/2, PI3K/Akt, and STATs, which subsequently reduce the retinal artery occlusion. Although, the molecular and cellular events glutamate-induced excitotoxicity and neuronal cell death; 2) sup- involved in ischemic retinal degeneration have been studied for pressing the production of free radicals and subsequent mitochon- several years, the identification of efficacious therapies still remains drial dysfunction; and 3) inhibiting glial activation, nitric oxide to be determined. In non-ocular systems, opioid-receptor-activation production, and proinflammatory cytokine production; the latter has been shown to elicit a protective effect during situations of action eventually negates the activation of caspases and apoptosis stress/ischemia. Based on the literature presented in this review, it and enhances neuronal survival. appears that opioid agonists act at multiple sites to block the delete- Although ischemia-induced-activation of signaling pathways rious effects of signaling molecules in ischemic conditions. In addi- for retina neurodegeneration and DOR-mediated retina neuropro- tion, endogenous opioids play a central role in neuroprotection tection requires further experimental proof, similar pathways have against a variety of injuries. Ideal neuroprotective agents against been shown to be active in non-ocular tissues. For example, studies retinal ischemia should be easy to administer, rapidly adsorbed, have shown that glutamate- and hypoxia-induced neuronal death of able to cross the blood-retinal barrier with minimal or no adverse cultured neocortical neurons from rats was reduced when -opioid side-effects. Such a neuroprotective agent should also activate en- agonists were present during the application of the insult [13, 40]. dogenous neuroprotective mechanisms, disrupt the ischemic cas- Additionally, DADLE, a selective -opioid-agonist, provided neu- cade at multiple points, and provide long-lasting protection against roprotection against oxidative injury in ischemic rat brain via at- an ischemic event. tenuation of nitric oxide [130]. Nitric oxide is an important signal- Recently, we and others have shown that retinal function and ing molecule, which protects vital organs such as liver, brain, and morphology are significantly maintained in the presence of mor- eye from ischemic damage. However; sustained levels of nitric phine against acute ischemia-induced injury. Moreover, studies oxide production result in direct tissue toxicity and contribute to have provided evidence that hypoxic preconditioning in the retina neuronal degeneration [131]. Three isoforms of NOS have been can up-regulate -opioid-receptors. Additionally, opioid-receptor cloned: constitutive (NOS-1 or nNOS); endothelial (NOS-3 or activation is required for the development of retinal ischemic pre- eNOS); and inducible (NOS-2 or iNOS). At the cellular level, under conditioning against ischemic injury. Based on the literature pre- pathological conditions, NOS-2 synthesizes excessive quantities of sented in this review, and data obtained in our laboratory, opioid nitric oxide, which combines chemically with superoxide to form agonists represent a novel class of drugs/agents that have the capac- the highly reactive and destructive peroxynitrite [132]. Nitrosyla- ity to counteract loss key neuronal elements in the retina. tion by peroxynitrite of cellular proteins, lipids, and DNA triggers apoptosis [133]. Alternatively, excessive production of nitric oxide CONFLICT OF INTEREST causes cytochrome release from the mitochondria and activates c The authors do not have a conflict of interest in any service or the caspase signaling pathway, thus triggering neuronal death product associated with this manuscript. through the caspase-activated DNase activation [134]. Studies have shown that DOR activation attenuated cytochrome c release in ACKNOWLEDGEMENTS severe hypoxic stress [38]. Based on the research performed on other organelles, it is likely that DOR activation may reduce the Supported in part by NIH/NEI grant EY019081 (SH) and an production of nitric oxide, attenuate cytochrome c release and de- unrestricted grant to MUSC from Research to Prevent Blindness, crease caspase activity, thus protecting the brain from ische- New York. The authors thankfully acknowledge Luanna Bartholo- mia/reperfusion injury. In the eye, roles of nitric oxide in opioid- mew, Ph.D. (MUSC-SEI), for critical review of the manuscript. mediated retinal neuroprotection against ischemic injury require REFERENCES additional study. + 2+ [1] Chen Y, Mestek A, Liu J, Hurley JA, Yu L. Molecular cloning and Alternatively, DOR activation decreases Na and Ca influx functional expression of a mu-opioid receptor from rat brain. Mol and decreases neuronal depolarization [35, 42, 135]. DOR activa- Pharmacol 1993; 44: 8-12. tion also decreases K+ efflux from ischemic cortical neurons [36, [2] Minami, M., and Satoh, M. Molecular biology of the opioid recep- 42], which protects the local network from further K+-dependent tors: structures, functions and distributions. Neurosci Res 1995; 23: depolarization due to excessive K+ ions in the extracellular space. It 121-45. is believed that the gain from protecting the local neuronal network [3] Howells RD, Kilpatrick DL, Bailey LC, Noe M, Udenfriend S. via decreased K+ efflux overrides the advantage of having individ- Proenkephalin mRNA in rat heart. Proc Natl Acad Sci USA 1986; + 83: 1960-3. ual neurons undergo protective hyperpolarization via K efflux [36, [4] Wamsley JK, Palacios JM, Kuhar MJ. Autoradiographic localiza- 42]. Further down in the ischemic cascade, DOR decreases excita- tion of opioid receptors in the mammalian retina. Neurosci Lett tory synaptic transmission via presynaptic mechanisms [136, 137], 1981; 27: 19-24. + postsynaptic mechanisms [138, 139], and a reduction in the Na and [5] Husain S, Potter DE, Crosson CE. Opioid-receptor-activation pro- Ca2+ influx [35, 42, 135, 138]. Finally, DOR activation maintains tects the retina from ischemic injury. Invest Ophthalmol Vis Sci intracellular homeostasis by decreasing mitochondrial respiratory 2009; 50: 3853-9. chain injury (induced by sodium azide) [140], and decreasing intra- [6] Husain S, Liou GI, Crosson CE. Opioid-receptor-activation: Sup- cellular free radical generation [112, 141]. Although some mecha- pression of ischemia/reperfusion-induced production of TNF-alpha in the retina. Invest Ophthalmol Vis Sci 2011; 52: 2577-83. 5924 Current Pharmaceutical Design, 2012, Vol. 18, No. 37 Husain et al.

[7] Schultz JE, Rose E, Yao Z, Gross, GJ. Evidence for involvement of [31] Peart JN, Gross ER, Gross GJ. Opioid-induced preconditioning: opioid receptors in ischemic preconditioning in rat hearts. Am J recent advances and future perspectives. Vascul Pharmacol 2005; Physiol 1995; 268: H2157-61. 42: 211-8. [8] Schultz JE, Gross GJ. Opioids and cardioprotection. Pharmacol [32] Rubaj A, Gustaw K, Zgodzinski W, Kleinrok Z, Sieklucka-Dziuba Ther 2001; 89, 123-37. M. The role of opioid receptors in hypoxic preconditioning against [9] Ferri S, Speroni E, Candeletti S, et al. Protection by opioids against seizures in brain. Pharmacol Biochem Behav 2000; 67: 65-70. gastric lesions caused by necrotizing agents. Pharmacology 1988; [33] Gannon RL, Terrian DM. U-50,488H inhibits dynorphin and glu- 36: 140-4. tamate release from guinea pig hippocampal mossy fiber terminals. [10] Mayfield KP, D'Alecy LG. Delta-1 opioid agonist acutely increases Brain Res 1991; 548: 242-7. hypoxic tolerance. J Pharmacol Exp Ther 1994; 268: 683-8. [34] Gross RA, Macdonald RL. Dynorphin A selectively reduces a large [11] Paradis P, Dumont M, Belichard P, Rouleau JL, Lemaire S, Brak- transient (N-type) calcium current of mouse dorsal root ganglion ier-Gingras L. Increased preproenkephalin A gene expression in the neurons in cell culture. Proc Natl Acad Sci USA 1987; 84: 5469- rat heart after induction of a myocardial infarction. Biochem Cell 73. Biol 1992; 70: 593-8. [35] Chao D, Bazzy-Asaad A, Balboni G, Salvadori S, Xia Y. Activa- [12] Chen TY, Goyagi T, Toung TJ, et al. Prolonged opportunity for tion of DOR attenuates anoxic K+ derangement via inhibition of ischemic neuroprotection with selective kappa-opioid receptor ago- Na+ entry in mouse cortex. Cereb Cortex 2008; 18: 2217-27. nist in rats. Stroke 2004; 35: 1180-5. [36] Chao D, Donnelly DF, Feng Y, Bazzy-Asaad A, Xia Y. Cortical [13] Zhang J, Gibney GT, Zhao P, Xia Y. Neuroprotective role of delta- delta-opioid receptors potentiate K+ homeostasis during anoxia and opioid receptors in cortical neurons. Am J Physiol Cell Physiol oxygen-glucose deprivation. J Cereb Blood Flow Metab 2007; 27: 2002; 282: C1225-34. 356-68. [14] Meriney SD, Gray DB, Pilar G. Morphine-induced delay of normal [37] Hong SS, Qian H, Zhao P, Bazzy-Asaad A, Xia Y. Anisomycin cell death in the avian ciliary ganglion. Science 1985; 228: 1451-3. protects cortical neurons from prolonged hypoxia with differential [15] Schmahl W, Funk R, Miaskowski U, Plendl J. Long-lasting effects regulation of p38 and ERK. Brain Res 2007; 1149: 76-86. of naltrexone, an opioid receptor antagonist, on cell proliferation in [38] Ma MC, Qian H, Ghassemi F, Zhao P, Xia Y. Oxygen-sensitive developing rat forebrain. Brain Res 1989; 486: 297-300. {delta}-opioid receptor-regulated survival and death signals: novel [16] Meriney SD, Ford MJ, Oliva D, Pilar G. Endogenous opioids insights into neuronal preconditioning and protection. J Biol Chem modulate neuronal survival in the developing avian ciliary gan- 2005; 280: 16208-18. glion. J Neurosci 1991; 11: 3705-17. [39] Tian XS, Zhou F, Yang R, Xia Y, Wu GC, Guo JC. Effects of [17] Liang BT, Gross GJ. Direct preconditioning of cardiac myocytes intracerebroventricular injection of delta-opioid receptor agonist via opioid receptors and KATP channels. Circ Res 1999; 84: 1396- TAN-67 or antagonist naltrindole on acute cerebral ischemia in rat. 1400. Sheng Li Xue Bao 2008; 60: 475-84. [18] Zhao P, Huang Y, Zuo Z. Opioid preconditioning induces opioid [40] Zhang J, Haddad GG, Xia Y. delta-, but not mu- and kappa-, opioid receptor-dependent delayed neuroprotection against ischemia in receptor activation protects neocortical neurons from glutamate- rats. J Neuropathol Exp Neurol 2006; 65: 945-52. induced excitotoxic injury. Brain Res 2000; 885: 143-53. [19] Rogers TJ, Peterson PK. Opioid G protein-coupled receptors: sig- [41] Zhang J, Qian H, Zhao P, Hong SS, Xia Y. Rapid hypoxia precon- nals at the crossroads of inflammation. Trends Immunol 2003; 24: ditioning protects cortical neurons from glutamate toxicity through 116-21. delta-opioid receptor. Stroke 2006; 37: 1094-9. [20] Bodnar RJ, Klein GE. Endogenous opiates and behavior: 2003. [42] Chao D, Bazzy-Asaad A, Balboni G, Xia Y. delta-, but not mu-, Peptides 2004; 25: 2205-56. opioid receptor stabilizes K(+) homeostasis by reducing Ca(2+) in- [21] Malinowski K, Shock EJ, Rochelle P, Kearns CF, Guirnalda PD, flux in the cortex during acute hypoxia. J Cell Physiol 2007; 212: McKeever KH. Plasma beta-endorphin, cortisol and immune re- 60-7. sponses to acute exercise are altered by age and exercise training in [43] Drago F, Panissidi G, Bellomio F, Dal Bello A, Aguglia E, Gor- horses. Equine Vet J Suppl 2006; 36: 267-73. gone G. Effects of opiates and opioids on intraocular pressure of [22] Stanojevic S, Mitic K, Vujic V, Kovacevic-Jovanovic V, Dimitri- rabbits and humans. Clin Exp Pharmacol Physiol 1985; 12: 107-13. jevic M. Beta-endorphin differentially affects inflammation in two [44] Drago F, Gorgone G, Spina F, et al. Opiate receptors in the rabbit inbred rat strains. Eur J Pharmacol 2006; 549: 157-65. iris. Naunyn Schmiedebergs Arch Pharmacol 1980; 315: 1-4. [23] Cui Y, Lee TF, Wang LC. State-dependent changes of brain en- [45] Selbach JM, Buschnack SH, Steuhl KP, Kremmer S, Muth-Selbach dogenous opioids in mammalian hibernation. Brain Res Bull 1996; U. Substance P and opioid peptidergic innervation of the anterior 40: 129-33. eye segment of the rat: an immunohistochemical study. J Anat [24] Drew KL, Rice ME, Kuhn TB, Smith MA. Neuroprotective adapta- 2005; 206: 237-42. tions in hibernation: therapeutic implications for ischemia- [46] Stone RA, Kuwayama Y, Laties AM. Regulatory peptides in the reperfusion, traumatic brain injury and neurodegenerative diseases. eye. Experientia 1987; 43: 791-800. Free Radic Biol Med 2001; 31: 563-73. [47] Drago F, Aguglia E, Dal Bello A, et al. Ocular instillation of [25] Drew KL, Buck CL, Barnes BM, Christian SL, Rasley BT, Harris naloxone increases intraocular pressure in morphine-addicted pa- MB. Central nervous system regulation of mammalian hibernation: tients: a possible test for detecting misuse of morphine. Experientia implications for metabolic suppression and ischemia tolerance. J 1985; 41: 266-7. Neurochem 2007; 102: 1713-26. [48] Murray RB, Adler MW, Korczyn AD. The pupillary effects of [26] Oeltgen PR, Nilekani SP, Nuchols PA, Spurrier WA, Su TP. Fur- opioids. Life Sci 1983; 33: 495-509. ther studies on opioids and hibernation: delta opioid receptor ligand [49] Fanciullacci M, Boccuni M, Pietrini U, Sicuteri F. The naloxone selectively induced hibernation in summer-active ground squirrels. conjunctival test in morphine addiction. Eur J Pharmacol 1980; 61: Life Sci 1988; 43: 1565-74. 319-20. [27] Govindaswami M, Brown SA, Yu J, et al. Delta 2-specific opioid [50] Russell KR, Wang DR, Potter DE. Modulation of ocular hydrody- receptor agonist and hibernating woodchuck plasma fraction pro- namics and iris function by bremazocine, a kappa opioid receptor vide ischemic neuroprotection. Acad Emerg Med 2008; 15: 250-7. agonist. Exp Eye Res 2000; 70: 675-82. [28] Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker [51] Wang D, Potter DE. Ocular action of an opioid peptide, DPDPE. J JM. Endogenous opioids: biology and function. Annu Rev Neuro- Ocul Pharmacol Ther 1996; 12: 131-9. sci 1984; 7: 223-55. [52] Russell KR, Potter DE. Dynorphin modulates ocular hydrodynam- [29] Maslov LN, Lishmanov YB. Change in opioid peptide level in the ics and releases atrial natriuretic peptide via activation of kappa- heart and blood plasma during acute myocardial ischaemia compli- opioid receptors. Exp Eye Res 2002; 75: 259-70. cated by ventricular fibrillation. Clin Exp Pharmacol Physiol 1995; [53] Moore TT, Potter DE. Kappa opioid agonist-induced changes in 22: 812-6. IOP: correlation with 3H-NE release and cAMP accumulation. Exp [30] Chien GL, Van Winkle DM. Naloxone blockade of myocardial Eye Res 2001; 73: 167-78. ischemic preconditioning is stereoselective. J Mol Cell Cardiol [54] Potter DE, Russell KR, Manhiani M. Bremazocine increases C- 1996; 28: 1895-1900. type natriuretic peptide levels in aqueous humor and enhances outflow facility. J Pharmacol Exp Ther 2004; 309: 548-53. Ocular Neuroprotection by Opioids Current Pharmaceutical Design, 2012, Vol. 18, No. 37 5925

[55] Chu TC, Potter DE. Ocular hypotension induced by electroacu- and clinical outcome. J Trauma 1995; 39: 879-85; discussion 885- puncture. J Ocul Pharmacol Ther 2002; 18: 293-305. 7. [56] Kurusu M, Watanabe K, Nakazawa T, et al. Acupuncture for pa- [80] Shohami E, Bass R, Wallach D, Yamin A, Gallily R. Inhibition of tients with glaucoma. Explore (NY) 2005; 1: 372-6. tumor necrosis factor alpha (TNFalpha) activity in rat brain is asso- [57] Chien GL, Mohtadi K, Wolff RA, Van Winkle DM. Naloxone ciated with cerebroprotection after closed head injury. J Cereb blockade of myocardial ischemic preconditioning does not require Blood Flow Metab 1996; 16: 378-84. central nervous system participation. Basic Res Cardiol 1999; 94: [81] Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases 136-43. and tumor necrosis factor alpha in glaucomatous optic nerve head. [58] Riazi-Esfahani M, Kiumehr S, Asadi-Amoli F, Lashay AR, Arch Ophthalmol 2000; 118: 666-73. Dehpour AR. Morphine pretreatment provides histologic protection [82] Yuan L, Neufeld AH. Tumor necrosis factor-alpha: a potentially against ischemia-reperfusion injury in rabbit retina. Retina 2008; neurodestructive cytokine produced by glia in the human glauco- 28: 511-7. matous optic nerve head. Glia 2000; 32: 42-50. [59] Martini SR, Kent TA. Hyperglycemia in acute ischemic stroke: a [83] Bonnet MP, Beloeil H, Benhamou D, Mazoit JX, Asehnoune K. vascular perspective. J Cereb Blood Flow Metab 2007; 27: 435-51. The mu opioid receptor mediates morphine-induced tumor necrosis [60] Bang OY, Saver JL, Buck BH, et al. Impact of collateral flow on factor and interleukin-6 inhibition in toll-like receptor 2-stimulated tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychia- monocytes. Anesth Analg 2008; 106: 1142-9, table of contents. try 2008; 79: 625-9. [84] Garcia I, Perez-Castillo A, Moreno J, Alemany S. Beta-endorphin [61] Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol inhibits interleukin-2 release and expression of interleukin-2 recep- 2005; 15: 234-40. tors in concanavalin A-stimulated splenic lymphocytes. Lym- [62] Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Me- phokine Cytokine Res 1992; 11: 339-45. lena J. Retinal ischemia: mechanisms of damage and potential [85] Takeba Y, Suzuki N, Kaneko A, Asai T, Sakane T. Endorphin and therapeutic strategies. Prog Retin Eye Res 2004; 23: 91-147. enkephalin ameliorate excessive synovial cell functions in patients [63] Roth S, Dreixler JC, Shaikh AR, Lee KH, Bindokas V. Mitochon- with rheumatoid arthritis. J Rheumatol 2001; 28: 2176-83. drial potassium ATP channels and retinal ischemic preconditioning. [86] Sheng WS, Hu S, Lokensgard JR, Peterson PK. U50,488 inhibits Invest Ophthalmol Vis Sci 2006; 47: 2114-24. HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) [64] Roth S, Li B, Rosenbaum PS, Gupta H, Goldstein IM, Maxwell production by human astrocytes. Biochem Pharmacol 2003; 65: 9- KM, Gidday JM. Preconditioning provides complete protection 14. against retinal ischemic injury in rats. Invest Ophthalmol Vis Sci [87] Sharma SK, Klee WA, Nirenberg M. Dual regulation of adenylate 1998; 39: 777-85. cyclase accounts for narcotic dependence and tolerance. Proc Natl [65] Zhang X, Cheng M, Chintala SK. Kainic acid-mediated upregula- Acad Sci USA 1975; 72: 3092-6. tion of matrix metalloproteinase-9 promotes retinal degeneration. [88] Standifer KM, Pasternak GW. G proteins and opioid receptor- Invest Ophthalmol Vis Sci 2004; 45: 2374-83. mediated signalling. Cell Signal 1997; 9: 237-48. [66] Osborne NN, Ugarte M, Chao M, et al. Neuroprotection in relation [89] Kim MS, Cheong YP, So HS, et al. Protective effects of morphine to retinal ischemia and relevance to glaucoma. Surv Ophthalmol in peroxynitrite-induced apoptosis of primary rat neonatal astro- 1999; 43 (Suppl 1): S102-28. cytes: potential involvement of G protein and phosphatidylinositol [67] Perez-Guijo V, Santos-Lacomba M, Sanchez-Hernandez M, Cas- 3-kinase (PI3 kinase). Biochem Pharmacol 2001; 61: 779-86. tro-Villegas Mdel C, Gallardo-Galera JM, Collantes-Estevez E. [90] Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adap- Tumour necrosis factor-alpha levels in aqueous humour and serum tations mediating opioid dependence. Physiol Rev 2001; 81: 299- from patients with uveitis: the involvement of HLA-B27. Curr Med 343. Res Opin 2004; 20: 155-7. [91] Kazmi SM, Mishra RK. Comparative pharmacological properties [68] de Kozak Y, Cotinet A, Goureau O, Hicks D, Thillaye-Goldenberg and functional coupling of mu and delta opioid receptor sites in B. Tumor necrosis factor and nitric oxide production by resident human neuroblastoma SH-SY5Y cells. Mol Pharmacol 1987; 32: retinal glial cells from rats presenting hereditary retinal degenera- 109-18. tion. Ocul Immunol Inflamm 1997; 5: 85-94. [92] Frey EA, Kebabian JW. A mu-opiate receptor in 7315c tumor [69] Tezel G, Li LY, Patil RV, Wax MB. TNF-alpha and TNF-alpha tissue mediates inhibition of immunoreactive prolactin release and receptor-1 in the retina of normal and glaucomatous eyes. Invest adenylate cyclase activity. Endocrinology 1984; 115: 1797-804. Ophthalmol Vis Sci 2001; 42: 1787-94. [93] North RA, Williams JT, Surprenant A, Christie MJ. Mu and delta [70] Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S. Determi- receptors belong to a family of receptors that are coupled to potas- nation of vitreous interleukin-1 (IL-1) and tumour necrosis factor sium channels. Proc Natl Acad Sci USA 1987; 84: 5487-91. (TNF) levels in proliferative diabetic retinopathy. Eye 2006; 20: [94] Twitchell WA, Rane SG. Nucleotide-independent modulation of 1366-9. Ca(2+)-dependent K+ channel current by a mu-type opioid recep- [71] Liu T, Clark RK, McDonnell PC, et al. Tumor necrosis factor- tor. Mol Pharmacol 1994; 46: 793-8. alpha expression in ischemic neurons. Stroke 1994; 25: 1481-8. [95] Wimpey TL, Chavkin C. Opioids activate both an inward rectifier [72] Hsu H, Xiong J, Goeddel DV. (1995) The TNF receptor 1- and a novel voltage-gated potassium conductance in the hippocam- associated protein TRADD signals cell death and NF-kappa B acti- pal formation. Neuron 1991; 6: 281-9. vation. Cell 81: 495-504. [96] Grudt TJ, Williams JT. kappa-Opioid receptors also increase potas- [73] Shen Y, Li R, Shiosaki K. Inhibition of p75 tumor necrosis factor sium conductance. Proc Natl Acad Sci USA 1993; 90: 11429-32. receptor by antisense oligonucleotides increases hypoxic injury and [97] Surprenant A, Shen KZ, North RA, Tatsumi H. Inhibition of cal- beta-amyloid toxicity in human neuronal cell line. J Biol Chem cium currents by noradrenaline, somatostatin and opioids in 1997; 272: 3550-3. guinea-pig submucosal neurones. J Physiol 1990; 431: 585-608. [74] Ding WX, Yin XM. Dissection of the multiple mechanisms of [98] Wilding TJ, Womack MD, McCleskey EW. Fast, local signal TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med 2004; transduction between the mu opioid receptor and Ca2+ channels. J 8: 445-54. Neurosci 1995; 15: 4124-32. [75] Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor [99] Hescheler J, Rosenthal W, Trautwein W, Schultz G. The GTP- signaling. Cell Death Differ 2003; 10: 45-65. binding protein, Go, regulates neuronal calcium channels. Nature [76] Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, 1987; 325: 445-7. Eisel U. Neurodegenerative and neuroprotective effects of tumor [100] Iglesias M, Segura MF, Comella JX, Olmos G. Mu-opioid receptor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF activation prevents apoptosis following serum withdrawal in differ- receptor 1 and TNF receptor 2. J Neurosci 2002; 22: RC216. entiated SH-SY5Y cells and cortical neurons via phosphatidylinosi- [77] Kramer M, Dadon S, Hasanreisoglu M, et al. Proinflammatory tol 3-kinase. Neuropharmacology 2003; 44: 482-92. cytokines in a mouse model of central retinal artery occlusion. Mol [101] Hou YN, Vlaskovska M, Cebers G, Kasakov L, Liljequist S, Teren- Vis 2009; 15: 885-94. ius L. A mu-receptor opioid agonist induces AP-1 and NF-kappa B [78] Tezel G. TNF-alpha signaling in glaucomatous neurodegeneration. transcription factor activity in primary cultures of rat cortical neu- Prog Brain Res 2008; 173: 409-21. rons. Neurosci Lett 1996; 212: 159-62. [79] Ertel W, Keel M, Bonaccio M, et al. Release of anti-inflammatory [102] Dortch-Carnes J, Potter DE. Delta-opioid agonist-stimulated inosi- mediators after mechanical trauma correlates with severity of injury tol phosphate formation in isolated, rabbit iris-ciliary bodies: role 5926 Current Pharmaceutical Design, 2012, Vol. 18, No. 37 Husain et al.

of G(i/o) proteins and Gbetagamma-subunits. Exp Eye Res 2003; [123] Fukunaga K, Kawano T. Akt is a molecular target for signal trans- 77: 647-52. duction therapy in brain ischemic insult. J Pharmacol Sci 2003; 92: [103] Chen L, Huang LY. Sustained potentiation of NMDA receptor- 317-27. mediated glutamate responses through activation of protein kinase [124] Dreixler JC, Hemmert JW, Shenoy SK, et al. The role of C by a mu opioid. Neuron 1991; 7: 319-26. Akt/protein kinase B subtypes in retinal ischemic preconditioning. [104] Welters ID, Fimiani C, Bilfinger TV, Stefano GB. NF-kappaB, Exp Eye Res 2009; 88: 512-21. nitric oxide and opiate signaling. Med Hypotheses 2000; 54: 263-8. [125] Alexaki VI, Charalampopoulos I, Kampa M, et al. Estrogen exerts [105] Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential neuroprotective effects via membrane estrogen receptors and rapid for opioid-induced cardioprotection: JAK2 as a mediator of Akt/NOS activation. FASEB J 2004; 18: 1594-6. STAT3, Akt, and GSK-3 beta. Am J Physiol Heart Circ Physiol [126] Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt 2006; 291: H827-34. pathway limits lipopolysaccharide activation of signaling pathways [106] Law PY, Wong YH, Loh HH. Molecular mechanisms and regula- and expression of inflammatory mediators in human monocytic tion of opioid receptor signaling. Annu Rev Pharmacol Toxicol cells. J Biol Chem 2002; 277: 32124-32. 2000; 40: 389-430. [127] Yu Y, Nagai S, Wu H, Neish AS, Koyasu S, Gewirtz AT. TLR5- [107] Centurion SA, Centurion LM, Souza ME, et al. Effects of ischemic mediated phosphoinositide 3-kinase activation negatively regulates liver preconditioning on hepatic ischemia/reperfusion injury in the flagellin-induced proinflammatory gene expression. J Immunol rat. Transplant Proc 2007; 39: 361-4. 2006; 176: 6194-201. [108] Gidday JM, Fitzgibbons JC, Shah AR, Park TS. Neuroprotection [128] Zhao L, Lee JY, Hwang DH. The phosphatidylinositol 3- from ischemic brain injury by hypoxic preconditioning in the neo- kinase/Akt pathway negatively regulates Nod2-mediated NF- natal rat. Neurosci Lett 1994; 168: 221-4. kappaB pathway. Biochem Pharmacol 2008; 75: 1515-25. [109] Kato H, Araki T, Murase K, Kogure K. Induction of tolerance to [129] Levresse V, Butterfield L, Zentrich E, Heasley LE. Akt negatively ischemia: alterations in second-messenger systems in the gerbil regulates the cJun N-terminal kinase pathway in PC12 cells. J Neu- hippocampus. Brain Res Bull 1992; 29: 559-65. rosci Res 2000; 62: 799-808. [110] Murry CE, Jennings RB, Reimer KA. Preconditioning with ische- [130] Yang Y, Xia X, Zhang Y, et al. delta-Opioid receptor activation mia: a delay of lethal cell injury in ischemic myocardium. Circula- attenuates oxidative injury in the ischemic rat brain. BMC Biol tion 1986; 74: 1124-36. 2009; 7: 55. [111] Whitlock NA, Agarwal N, Ma JX, Crosson CE. Hsp27 upregula- [131] Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH. tion by HIF-1 signaling offers protection against retinal ischemia in Mechanisms of nitric oxide-mediated neurotoxicity in primary rats. Invest Ophthalmol Vis Sci 2005; 46: 1092-8. brain cultures. J Neurosci 1993; 13: 2651-61. [112] Peng PH, Huang HS, Lee YJ, Chen YS, Ma MC. Novel role for the [132] Beckman JS, Koppenol WH. Nitric oxide, superoxide, and per- delta-opioid receptor in hypoxic preconditioning in rat retinas. J oxynitrite: the good, the bad, and ugly. Am J Physiol 1996; 271: Neurochem 2009; 108: 741-54. C1424-37. [113] Husted TL, Govindaswami M, Oeltgen PR., Rudich SM, Lentsch [133] Muijsers RB, Folkerts G, Henricks PA, Sadeghi-Hashjin G, Ni- AB. A delta2-opioid agonist inhibits p38 MAPK and suppresses ac- jkamp FP. Peroxynitrite: a two-faced metabolite of nitric oxide. tivation of murine macrophages. J Surg Res 2005; 128: 45-9. Life Sci 1997; 60: 1833-45. [114] Welters ID, Menzebach A, Goumon Y, et al. Morphine inhibits [134] Ryter SW, Kim HP, Hoetzel A, et al. Mechanisms of cell death in NF-kappaB nuclear binding in human neutrophils and monocytes oxidative stress. Antioxid Redox Signal 2007; 9: 49-89. by a nitric oxide-dependent mechanism. Anesthesiology 2000; 92: [135] Keating DJ, Rychkov GY, Adams MB, Holgert H, McMillen IC, 1677-84. Roberts ML. Opioid receptor stimulation suppresses the adrenal [115] Muller DL, Unterwald EM. In vivo regulation of extracellular sig- medulla hypoxic response in sheep by actions on Ca(2+) and K(+) nal-regulated protein kinase (ERK) and protein kinase B (Akt) channels. J Physiol 2004; 555: 489-502. phosphorylation by acute and chronic morphine. J Pharmacol Exp [136] Bie B, Zhu W, Pan ZZ. Rewarding morphine-induced synaptic Ther 2004; 310: 774-82. function of delta-opioid receptors on central glutamate synapses. J [116] Kikuchi M, Tenneti L, Lipton SA. Role of p38 mitogen-activated Pharmacol Exp Ther 2009; 329: 290-6. protein kinase in axotomy-induced apoptosis of rat retinal ganglion [137] Glaum SR, Miller RJ, Hammond DL. Inhibitory actions of delta 1-, cells. J Neurosci 2000; 20: 5037-44. delta 2-, and mu-opioid receptor agonists on excitatory transmis- [117] Levkovitch-Verbin H, Harizman N, Dardik R, Nisgav Y, Vander S, sion in lamina II neurons of adult rat spinal cord. J Neurosci 1994; Melamed S. Regulation of cell death and survival pathways in ex- 14: 4965-71. perimental glaucoma. Exp Eye Res 2007; 85: 250-8. [138] Chao D, Balboni G, Lazarus LH, Salvadori S, Xia Y. Na+ mecha- [118] Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP. nism of delta-opioid receptor induced protection from anoxic K+ Global ischemia activates nuclear factor-kappa B in forebrain neu- leakage in the cortex. Cell Mol Life Sci 2009; 66: 1105-15. rons of rats. Stroke 1997; 28: 1073-80; discussion 1080-1. [139] Pamenter ME, Buck LT. delta-Opioid receptor antagonism induces [119] Schmidt KN, Amstad P, Cerutti P, Baeuerle PA. The roles of hy- NMDA receptor-dependent excitotoxicity in anoxic turtle cortex, J drogen peroxide and superoxide as messengers in the activation of Exp Biol 2008; 211: 3512-7. transcription factor NF-kappa B. Chem Biol 1995; 2: 13-22. [140] Zhu M, Li MW, Tian XS, Ou XM, Zhu CQ, Guo JC. Neuroprotec- [120] Kaltschmidt C, Kaltschmidt B, Baeuerle PA. Stimulation of tive role of delta-opioid receptors against mitochondrial respiratory ionotropic glutamate receptors activates transcription factor NF- chain injury. Brain Res 2009; 1252: 183-91. kappa B in primary neurons. Proc Natl Acad Sci USA 1995; 92: [141] Tsao LI, Ladenheim B, Andrews AM, Chiueh CC, Cadet JL, Su 9618-22. TP. Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the [121] Kitaoka Y, Kwong JM, Ross-Cisneros FN, et al. TNF-alpha- long-term loss of dopamine transporters induced by multiple ad- induced optic nerve degeneration and nuclear factor-kappaB p65. ministrations of methamphetamine: involvement of opioid recep- Invest Ophthalmol Vis Sci 2006; 47: 1448-57. tors and reactive oxygen species. J Pharmacol Exp Ther 1998; 287: [122] Schabbauer G, Tencati M, Pedersen B, Pawlinski R, Mackman N. 322-31. PI3K-Akt pathway suppresses coagulation and inflammation in en- dotoxemic mice. Arterioscler Thromb Vasc Biol 2004; 24: 1963-9.

Received: May 2, 2012 Accepted: May 24, 2012

View publication stats