Review Cite This: ACS Chem. Neurosci. 2019, 10, 182−189
pubs.acs.org/chemneuro
DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe Parvez Alam,†,∥ Subhomoi Borkokoty,† Mohammad Khursheed Siddiqi,‡ Aquib Ehtram,† Nabeela Majid,‡ Moin Uddin,§ and Rizwan Hasan Khan*,‡ †
Kusuma School of Biological Sciences, Indian Institute of Technology, Hauz Khas, New Delhi 110016, India Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India § Department of IlmulAdvia (Unani Pharmacology), Ajmal Khan Tibbiya College, Aligarh Muslim University, Aligarh 202002, India
ACS Chem. Neurosci. 2019.10:182-189. Downloaded from pubs.acs.org by OPEN UNIV OF HONG KONG on 01/28/19. For personal use only.
‡
ABSTRACT: Opium has found great use medicinally for its analgesic properties and has been witnessed as one of the most popular medications used in psychiatry. Opium derivatives have been shown as efficacious for relieving pain and the treatment of epileptic seizures, but progressive research toward their use in the treatment of neurodegenerative diseases remain elusive. To gain more insight into the other properties of opium such as anti-inflammatory properties, herein we discuss basic information regarding opium, opium content and mechanism of action, pharmacology of opium derivatives, the role of opium in the prevention of neurodegeneration, and adverse effects of opium derivatives on neuronal health.
KEYWORDS: Opium, neuroscience, neurodegeneration, medicine, mechanism
■
INTRODUCTION Opium is the dried latex obtained from the opium poppy. Opium latex contains morphine, codeine, thebaine, papaverine ,and noscapine (Figure 1). Since prehistoric times, opiates have been used for medicinal purposes including relieving pain in cancer, spasms from tetanus, and pain associated with menstruation and childbirth. The plant papaver has been known for its medicinal benefits as have several other benzylisoquinoline alkaloids (BIAs) with potent pharmacological properties including the vasodilator papaverine, the cough suppressant and potential anticancer drug noscapine, and the antimicrobial agent sanguinarine. The collection of opium has been active since approximately 3400 BCE. The oldest archeological occurrence of poppy species was documented for the wild poppy, Papaver setigerum. Many alkaloids are being derived from opium but the only important opiates include morphine (10%) and codeine. Morphine was identified first as the active pharmacological ingredient of opium (making up between 9% and 14% of opium) in the early 1800s and was then consumed by patients with malaria for pain relief because it was cheap and easily available although the quinones specific for malaria treatment were present at that time but they were not affordable. Heroin (diacetylmorphine) was further synthesized from morphine modifications in the late 1800s in an attempt to develop a nonaddicting cough suppressant which was 5−10 times more potent as morphine yet safer. Papaverine, an opium derivative, is occasionally used as a vasodilator. In the Odyssey, Homer refers to a curative substance, which was administered to Helena as a remedy against grief and grudge. Similarly, the classical medical writings of Dioscurides © 2018 American Chemical Society
(1st century) and Galen (129−199) have referred to the narcotic analgesic properties of opium.1 And it was Paracelcus (1493−1541) a Swiss German alchemist who observed that certain analgesic opium alkaloids are far more soluble in alcohol than in water which led to tinctura laudanum, allowing for easy medicinal delivery2,3 and thus paving the way for opium’s regimented use in medicine. In the following century, Thomas Sydenham (1624−1689) recommended opium against hysteria and mania.4 Then, in general, the 18th century witnessed opium as one of the more popular medications used in psychiatry.5−7 In 1991, Weber and Emrich published an extraordinary review of opiate treatment in psychiatric disorders.8 Previously, our group has reported the effect of small molecules in preventing amyloid formation in proteins and their ability to protect neuronal cells against amyloid induced cytotoxicity.9−15 In this Review, we discuss some basic information regarding opium, opium content and mechanism of action, pharmacology of opium derivatives, the role of opium in prevention of neurodegeneration, and adverse effects of opium derivatives on the neuronal health, and we attempt to widely disperse data into one easily accessible format for the “Classics in Chemical Neuroscience” series. Received: October 10, 2018 Accepted: November 7, 2018 Published: November 7, 2018 182
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience
Figure 1. Structures of the most common opium alkaloids.
Figure 2. Experimental structures of the classical opioid receptors: KOP (PDB ID: 4DJH),30 MOP (PDB ID: 5C1M),31 and DOP (PDB ID: 4N6H)32 with NOP (PDB ID: 4EA3)33 and their major targets in the nervous system.
■
pain neurotransmitters.18 Opioids reduce the intensity and unpleasantness of pain. They produce their effects by activating specific G protein-coupled receptors in the brain, spinal cord, and peripheral nervous system. Opioids have specific binding to distinct receptors. Based on their differences in opioid potency, selective antagonism, and stereospecificity of opiate actions, opioid receptors (OPs) can be classified into three major classes based on their affinity for various opioid ligands and in their distribution in the nervous system: δ-opioid (DOP), κ-opioid (KOP), and μ-opioid (MOP) (Figure 2). These are termed as classical opioid receptors.18,19 However, there is a fourth type of OP termed as nonclassical, i.e. nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). NOP shares significant sequence homology with the classical opioid receptors.20 The ε-, ι-, λ-, and ζ-
OPIUM CONTENT AND MECHANISM OF ACTION Opium contains both nonalkaloid and alkaloid constituents. The nonalkaloid part is made up of water (∼5−20%), various sugars (∼20%), and several simple organic acids such as fumaric acid, lactic acid, oxaloacetic acid, and meconic acid. While the alkaloid content is approximately 10−20% with more than 40 individual alkaloids including major alkaloids such as morphine, codeine, thebaine, etc. and minor alkaloids such as aporphines, rhoeadines, tetrahydroisoquinolines, etc.16 Opioids can be classified based on their source, chemical structure, and function.17,18 Opioids can act as agonists, antagonists, agonists/antagonists, or partial agonists. Agonist activity at opioid receptors acts to open potassium channels and prevent the opening of voltage-gated calcium channels. This reduces neuronal excitability and inhibits the release of 183
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
ACS Chemical Neuroscience
Review
■
MEDICINAL CHEMISTRY AND PHARMACOLOGY OF OPIUM As we have seen in Table 1, opioids can be classified as agonist, antagonist, partial agonist, or antagonist and mixed action.
receptors are few of the novel but poorly characterized opioid receptors. Initially considered to be an opioid receptor, the σreceptor is no longer classified with the opioid receptors because it displays neither the stereoselectivity characteristic of opioid receptors nor antagonism by opioid antagonists.21 OPs are coupled to G proteins (G1 and G0), and they interact with these G proteins to inhibit adenylate cyclase, an enzyme that promotes the formation of the intracellular messenger cyclic adenosine 3′,5′-monophosphate (cyclic AMP). G proteins also may mediate the inhibitory effects of opioids on voltage-gated calcium channels and their activating effects on inwardly rectifying potassium channels. Inhibition of calcium channels may lead to a decrease in the release of neurotransmitters such as substance P, which mediates pain signals.22 DOPs (agonist delta-alanine-delta-leucine-enkephalin) are distributed throughout the central nervous system (CNS). DOP density varies in different brain regions: the highest densities can be found in the olfactory bulb, neocortex, caudate putamen, and nucleus accumbens, and to a lesser degree the thalamus, hypothalamus, and brain stem.20 This receptor is involved in the antinociceptive/analgesic actions of some opioids. Activation of DOP results in decreased presynaptic Ca2+ influx, which inhibits release of neurotransmitters, and an increase in postsynaptic K+ efflux, which hyperpolarizes the neuron.23 KOPs (agonist ketocyclazocine) are widely expressed throughout the brain, spinal cord, and peripheral tissues. They are responsible for spinal analgesia, sedation, dyspnea, dependence, dysphoria, and respiratory depression. Activation of KOPs primarily leads to an inhibition of adenylyl cyclase through the Gα subunit and induces increased potassium channel conductance and decreased calcium conductance via the Gβγ subunit. Modulation of these ion channels results in decreased action potential generation and neurotransmitter release.24,25 MOP receptors are located throughout the central nervous system including the cerebral cortex, amygdala (of the limbic system), and putamen of the basal ganglia (highest density).26 MORs modulate intracellular effectors through inhibitory Go/ Gi proteins as opioid agonists bind. In turn, receptor signaling is readily terminated by several cellular regulatory processes such as phosphorylation, desensitization, endocytosis, and downregulation.27 Antagonists like naloxone and naltrexone block MOP, whereas agonists like methadone and buprenorphine partially activate the MOP.27 Major side effects associated with MOP agonists include respiratory depression, while with MOP antagonist side effects such as peristalsis and constipation are common. MOP opioids also have effects on the cardiovascular system, thermoregulation, hormone secretion, and immune function.28 The NOP receptor sequence is approximately 50−60% identical to the classic opioid receptors.29 N/OFQ and its receptor are widely expressed throughout both the central and the peripheral nervous system.20 The N/OFQ (O, orphanin; F, phenylalanine; and Q, glutamine) peptide activates the NOP receptor and triggers intracellular signaling events, including inhibition of adenylyl cyclase and activation of various kinases like protein kinase C (PKC) and p38 mitogen-activated protein kinase and modulation of calcium and potassium channel conductance.29
Table 1. Classification of Opioids source
natural semisynthetic synthetic
chemical structure
phenanthrenes benzomorphans diphenylpropylamines phenylpiperidines anilidopiperidines oripavine derivatives
function
morphinan derivatives synthetic analogue of codeine pure agonists partial agonists mixed action antagonists
morphine, codeine tramadol, heroin, oxycodone, oxymorphone, and buprenorphine entanyl, pethidine, and dextropropoxyphene morphine, codeine, heroin, hydromorphone, and oxycodone pentazocine and phenazocine propoxyphene, methadone, levo-Αacetylmethadol, and loperamide meperidine fentanyl, alfentanil, and sufentanil etorphine, dihydroetorphine, and buprenorphine levorphanol and butorphanol tramadol morphine and codeine buprenorphine pentazocine, nalbupine, and butorphanol naxolone
Their activity differs owing to their action on different opioid receptors as well as genetic differences in opioid receptor sensitivity.24 Morphine, a classic example of a natural opioid, has agonistic actions at the μ-, κ-, and δ-receptors.16 Being on the World Health Organization (WHO) essential drugs list, it is widely used as an analgesic commonly administered by different routes such as intramuscular, intravenous, or oral. Major features of morphine and morphine-like agonists in the CNS include analgesia, drowsiness, euphoria, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia.16,34 Morphine (285.34 g mol−1) has an oral bioavailability of 30%−75%, plasma elimination half-life of 2−3.5 h, and octanol−water partition coefficient of 0.7. Morphine is chiefly metabolized through conjugation reactions with UGT2B7 (UDP-glucuronosyltransferase-2B7) enzyme, and hence, any genetic polymorphism of UGT2B7 may affect the action of morphine.35 The contributor of analgesic activity of morphine is an active metabolite of the UGT2B7 pathway, morphine-6-glucuronide (M-6-G). M-6-G is responsible for sedation and nausea in patients with impaired renal excretory function (as it is excreted in the urine).34,36 A more watersoluble morphine metabolite (octanol−water partition coefficient of 1.28), hydromorphone, is eight times more active than morphine, and it does not have an active renally eliminated metabolite.16,34 Naloxone (327.38 g mol−1) is a competitive μ-receptor antagonist to opioids in the central nervous system. Naloxone also has been shown as an antagonist at other opioid receptors κ and δ but with a higher affinity for the μ receptor.24 Used as an antidote for opioid overdose, it has parenteral, intranasal, pulmonary, or orotracheal intubation route of administration.37 Naloxone is a potent inhibitor of the UGT2B7 pathway and thereby reduces the effect of morphine by altering M-6-G production; however, naloxone has no effect if opioids are not 184
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience present in a person.24 In naloxone postoperative patients, various adverse effects include cardiac disorders, gastrointestinal disorders, nervous system disorders, psychiatric disorders, respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders, and vascular disorders.37 Naloxone is metabolized in the liver and primarily undergoes glucuronidation to form naloxone-3-glucuronide and is excreted through urine (24−37% excreted as metabolites within first 6 h).38 Naloxone has low oral bioavailability (∼2%) due to extensive first-pass metabolism.39,40 The mixed agonist−antagonist and partial agonist buprenorphine (467.64 g mol−1) is a semisynthetic opioid, has a poor bioavailability with extensive first pass effect by the liver, but has excellent sublingual bioavailability due to high lipid solubility.16,39 This potent analgesic is a high-affinity partial μreceptor agonist and high-affinity δ- and κ-receptor antagonist and has moderate affinity at NOP receptors.41 As an agonist, buprenorphine is 30 times more potent than morphine. It also has low oral bioavailability due to extensive first-pass metabolism and hence is administered through sublingual mode.18 The primary mode of elimination of buprenorphine is through feces, with approximately 10−30% excreted in urine.42 Common buprenorphine adverse effects may include sedation, nausea and/or vomiting, dizziness, headache, and respiratory depression.24 Buprenorphine is also used as one of the medications to manage withdrawal from opioid drugs.43 Butorphanol (327.46 g mol−1) is an example of mixed agonist-antagonist opioid analgesic. It has an affinity for μ-, δ-, and κ-opioid receptor subtype. Butorphanol exhibits pure agonistic activity at the κ-receptor and antagonistic activity at the δ − receptor, while at μ-receptor it acts as a partial agonist.44 As an agonist, subcutaneous butorphanol is 3 to 5 times as potent as morphine and as an antagonist 15 to 25 times as potent as mixed agonist-antagonist opioid analgesic, pentazocine in human.45 Butorphanol is extensively metabolized in humans, mainly to hydroxybutorphanol. Butorphanol is excreted through the urinary (about 70%) and biliary (about 11−14%) mode of elimination. Adverse effects include sedation, nausea, respiratory depression, and psychotomimetic reactions.45 Tramadol (263.381 g mol−1), a synthetic 4-phenylpiperidine analogue of codeine, acts on the μ-opioid receptor as a weak agonist.46,47 However, its metabolite M1 has 300 times more affinity for the μ-opioid receptor as compared to the parent compound of tramadol. The other mechanisms by which tramadol acts on the central nervous system, including inhibition of reuptake of serotonin and norepinephrine, are contributed by the enantiomers of tramadol, (+)-tramadol and (−)-tramadol, respectively.47,48 Tramadol and its metabolites are mainly excreted via the kidneys.49 Tramadol is used primarily as an analgesic but is also seen as a useful agent in the management of heroin withdrawal.43 The extended-release (ER) formulation of tramadol is more effective than clonidine and comparable to buprenorphine in reducing opioid withdrawal symptoms.50
roles in attenuating neurodegeneration. Nootropic roles of opium derivatives are presented in Table 2 and discussed thereafter in detail. Table 2. Opium Derivatives and Their Nootropic Effect opium derivatives
nootropic effect
DM DM and DX have anticonvulsant effects that suppress seizures analogues induced by electroshock51−53 DM prevents seizures, mortality, and hippocampal cell loss in a dose-dependent manner54 DM minimizes the toxicity of the glutamate on the neuronal cells54 DX attenuates both morphological and chemical evidence of glutamate neurotoxicity in murine neocortical cell cultures54 3-HM neuroprotective against endotoxin-induced DA neurotoxicity55 nootropic to DA neurons in primary mixed mesencephalic neuro-glial cultures56 causes the release of certain nootropic factors (i.e., EGF, GDNF, TGF-β1, TGF-α1, and ADNF) from astroglia, exerting nootropic effect on DA neurons55 most potent in restoring DA neuronal loss and DA depletion as well as in attenuating behavioral damage55 increases the levels of nootropic factors and decreases the production of reactive oxygen species in LPS and MPTP PD models55 naloxone attenuate microglial activation in a dose-dependent manner57 attenuates cytokines that block the astrocyte activation, decreasing the brain vulnerability to epilepsy58 inhibits microglia driven neural inflammation59
DM Analogues. Opium derivatives have also been found to be involved in the treatment of epileptic seizures known as anticonvulsants. Dextromethorphan (DM; 3-methoxy-17methylmorphinan) and its metabolite dextrorphan (DX) have been reported to have anticonvulsant effects that suppress seizures induced by electroshock.51−53 Most studies confirm that DX is several times more potent than DM as an anticonvulsant.51 This may be due to the in vivo conversion of DM to DX significantly contributing toward the anticonvulsant activity of the parent molecule. Both molecules show an affinity toward σ-receptors, the binding that is responsible for the anticonvulsant properties. DM has 2−5-fold higher affinity than DX, whereas the anticonvulsant property of DX is higher than that of DM.60 Thus, the mechanism underlying the anticonvulsant effect remains undetermined. Both anticonvulsive and proconvulsive actions have been reported for the σreceptor binding that is responsible for the neuroprotective behavior.51 Earlier studies have suggested that DM prevents seizures, mortality, and hippocampal cell loss in a dose-dependent manner. This could be explained by the anticonvulsant properties of the molecule that minimizes the toxicity of the glutamate on the neuronal cells by inhibiting NMDA receptors.54 DM manages to inhibit NMDA receptor by acquiring a noncompetitive antagonist site of the receptor. On the contrary, DX is a more potent ligand toward the noncompetitive antagonist site of the NMDA receptor and is constant with the anticonvulsant effects in vivo.54,61 The dextrorotatory morphinan opioid, dextrorphan, which has recently been reported to block the excitation of cortical neurons by N-methyl-D-aspartate, was found at 10−100 μM concentrations to attenuate both morphological and chemical evidence of glutamate neurotoxicity in murine neocortical cell cultures.54
■
NOOTROPISM OF OPIUM DERIVATIVES Nootropic is a term used for the exploitation of medications or wholesome supplements that positively affect brain function. Various pharmaceutical compounds are available in the market, which have been exploited for their neuroprotective properties by altering specific neurotransmitters or opioid receptor binding. Several opium derivatives have been found to play 185
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience 3-HM. Progressive research for the development of effective therapeutics against neurodegeneration is limited. A structural analogue of DM, 3-HM, which lacks methyl groups at O and N sites, showed prominent results in the treatment of Parkinson’s disease (PD) and showed neuroprotective properties among the DM analogues available.55 Studies showed that 3-HM was more potent in restoring neuroprotection against endotoxininduced neurotoxicity than DM, its parent molecule.56 The nootropic effect of 3-HM was specifically glial dependent, and 3-HM failed to restore any protective impact in neuronenriched cultures. 3-HM was neuroprotective against endotoxin-induced dopamine (DA) neurotoxicity and also to DA neurons in primary mixed mesencephalic neuro-glial cultures.55,56 Furthermore, 3-HM caused the release of certain nootropic factors (i.e., EGF, GDNF, TGF-β1, TGF-α1, and ADNF) from astroglia, exerting neuroprotective effect of 3-HM on DA neurons. Glial cells, especially astroglia, protect stressed DA neurons through the production of various nootropic factors that counter oxidative stress in substantia nigra pars in PD.55 One potential therapeutic intervention will be to stimulate astroglia to produce these nootropic factors to rescue damaged neurons.55 The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of endotoxin-induced production of an array of proinflammatory and neurotoxic factors. Thus, 3HM provides neuroprotection by acting on two different cell targets: a nootropic effect mediated by astroglia and an antiinflammatory effect mediated by inhibition of microglial activation.55 Several investigations for the neuroprotective property of analogues of dextromethorphan (DM) in endotoxin-lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to classify neuroprotective drugs for PD have been done.55 In vivo studies on the two models showed that daily doses of DM metabolite protected DA neurons in substantia nigra pars compacta and restored DA levels in striatum. 3-HM, was found to be the most effective in restoring DA neuronal loss and DA depletion as well as in attenuating behavioral damage. By increasing the gene expression of various nootropic factors, and decreasing the production of ROS (reactive oxygen species), 3-HM showed the neuroprotective properties in LPS and MPTP PD models.55,62 Due to its high efficacy and low toxicity, 3-HM could be a novel therapy for PD. Naloxone. The role of inflammation has been long established in the groups of epileptic neurological disorders.63 Primary symptoms commonly includes episodes of epileptic seizures. Rapid astrocyte and microglial activation precedes the seizures and hippocampal neurodegeneration which plays a significant role in epileptogenesis.64,65 The precise mechanism of microglial activation still remains elusive. Cytokine production is a common phenomenon by glia when the seizures are associated with neuronal injury.66 Status epilepticus (SE) induced cytokine production in postnatal day 15 (PN 15) was studied, where IL-1β and S-100β levels were found to be strongly alleviated.58,67 Naloxone, a potential opioid receptor antagonist, has been investigated to attenuate microglial activation in a dose-dependent manner.57 The studies suggested PN 15 SE induced glial derived IL-1β and S100β could be minimized when given in optimal doses.58 Naloxone driven attenuation of cytokines blocks the astrocyte activation, thereby decreasing the brain vulnerability to epilepsy.58
Endotoxin driven inflammation leads to the activation of microglia, which in turn produces proinflammatory cytokines and neurotoxic factors, such as TNF-α, NO, IL-10, superoxide, and free radicals, which subsequently mediates dopaminergic neurodegeneration.68 Naloxone has been shown to be a neuroprotective agent through the inhibition of microglia driven neural-inflammation.59 The underlying mechanism lies with the inhibition of cytokines and neurotoxic factors from activated microglial cells.69
■
DARK SIDE OF OPIUM DERIVATIVES IN NEURODEGENERATION There are several reports claiming the induction of apoptosis by the majority of opium derivatives. High doses of morphine during chronic treatment induce apoptosis in both neurons and microglial cells.70 The cytotoxicity of morphine has been found to be dose-dependent where a single dose of morphine did not induce apoptosis but the administration of large morphine doses induced apoptosis in neuronal cells.70,71 The morphological studies showed that chronic morphine treatment leads to substantial injuries in cerebral cortex and hippocampus. This eventually contributed to the reduction in dendritic complexity and decreased dendritic growth in the cerebral cortex and hippocampus72 Based on animal model studies, the most symptoms observed in DM abusers are caused by DX, a major metabolite, which binds to the same central nervous system receptors as a major metabolite of DM, phencyclidine (PCP). Hyperlocomotor activity is observed in the mice offspring when exposed to DM during prenatal stages. Marked behavioral depression is demonstrated when these offspring received additional DM.51,62 Pathological damage in the posterior cingulate cortex and retrosplenial cortex of the rat brain has been reported with a single treatment with noncompetitive NMDA receptor antagonists such as MK-801, PCP, or ketamine. In contrast, oral administration of high doses of DM does not produce neuropathological changes as reported for other NMDA receptor antagonists, suggesting that there are route-specific effects on the disposition of DM and its metabolites in rat brain73
■
CONCLUSION Opium derivatives act as potential agents toward neuroprotection. In this Review, the mechanism of their action has been evaluated that supports the idea that opium derivatives upon binding to their respective receptors cause the decreased influx of calcium which can be exploited for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. As we know there occur rapid and sustained increase in cytosolic calcium level because of amyloid oligomer formation during neurodegenerative diseases. The increased calcium level also triggers the rapid transformation of protofibrils into mature amyloid fibrils. Despite their negative effects on overdosage that are comparatively less than their beneficial effects, they can be included by pharmacists in the formulation of antiaggregating drugs for the treatment of various neurodegenerative diseases. There is an urgent need to design drug molecules based on opium contents, and their neuroprotective potential must be explored in animal models in order to have improved therapy for neurodegenerative diseases in future. 186
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience
■
(2018) Stabilizing proteins to prevent conformational changes required for amyloid fibril formation. J. Cell. Biochem., DOI: 10.1002/jcb.27576. (13) Siddiqi, M. K., Alam, P., Chaturvedi, S. K., Khan, M. V., Nusrat, S., Malik, S., and Khan, R. H. (2018) Capreomycin inhibits the initiation of amyloid fibrillation and suppresses amyloid induced cell toxicity. Biochim. Biophys. Acta, Proteins Proteomics 1866 (4), 549− 557. (14) Alam, P., Siddiqi, M. K., Chaturvedi, S. K., Zaman, M., and Khan, R. H. (2017) Vitamin B12 offers neuronal cell protection by inhibiting Aβ-42 amyloid fibrillation. Int. J. Biol. Macromol. 99, 477− 482. (15) Chaturvedi, S. K., Alam, P., Khan, J. M., Siddiqui, M. K., Kalaiarasan, P., Subbarao, N., Ahmad, Z., and Khan, R. H. (2015) Biophysical insight into the anti-amyloidogenic behavior of taurine. Int. J. Biol. Macromol. 80, 375−384. (16) Schiff, P. L. (2002) Opium and its alkaloids. Am. J. Pharm. Educ. 66 (2), 186. (17) Akhgari, M., Etemadi-Aleagha, A., and Jokar, F. (2016) Street level heroin, an overview on its components and adulterants. In Neuropathology of Drug Addictions and Substance Misuse 1, 867−877. (18) Lee, M. C., and Abrahams, M. (2012) Pain and analgesics. In Clinical Pharmacology, 11th ed., pp 278−294. (19) Reisine, T., and Bell, G. I. (1993) Molecular biology of opioid receptors. Trends Neurosci. 16 (12), 506−10. (20) McDonald, J., and Lambert, D. G. (2013) Opioid mechanisms and opioid drugs. Anaesthesia & Intensive Care Medicine 14 (11), 505− 509. (21) Corbett, A. D., Henderson, G., McKnight, A. T., and Paterson, S. J. (2006) 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br. J. Pharmacol. 147 (Suppl 1), S153−62. (22) Knapp, C. M. (2002) Opiates. In Encyclopedia of the Human Brain, pp 729−739. (23) Peppin, J. F., and Raffa, R. B. (2015) Delta opioid agonists: a concise update on potential therapeutic applications. J. Clin. Pharm. Ther. 40 (2), 155−66. (24) Trescot, A. M., Datta, S., Lee, M., and Hansen, H. (2008) Opioid pharmacology. Pain Physician 11 (2 Suppl), S133−53. (25) Wang, Y. H., Sun, J. F., Tao, Y. M., Chi, Z. Q., and Liu, J. G. (2010) The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol. Sin. 31 (9), 1065−70. (26) Liao, D., Lin, H., Law, P. Y., and Loh, H. H. (2005) Mu-opioid receptors modulate the stability of dendritic spines. Proc. Natl. Acad. Sci. U. S. A. 102 (5), 1725−30. (27) Contet, C., Kieffer, B. L., and Befort, K. (2004) Mu opioid receptor: a gateway to drug addiction. Curr. Opin. Neurobiol. 14 (3), 370−8. (28) McDonald, J., and Lambert, D. G. (2005) Opioid receptors. Continuing Education in Anaesthesia Critical Care & Pain 5 (1), 22−25. (29) Donica, C. L., Awwad, H. O., Thakker, D. R., and Standifer, K. M. (2013) Cellular mechanisms of nociceptin/orphanin FQ (N/ OFQ) peptide (NOP) receptor regulation and heterologous regulation by N/OFQ. Mol. Pharmacol. 83 (5), 907−18. (30) Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., Liu, W., Thompson, A. A., Huang, X. P., Carroll, F. I., Mascarella, S. W., Westkaemper, R. B., Mosier, P. D., Roth, B. L., Cherezov, V., and Stevens, R. C. (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485 (7398), 327−32. (31) Huang, W., Manglik, A., Venkatakrishnan, A. J., Laeremans, T., Feinberg, E. N., Sanborn, A. L., Kato, H. E., Livingston, K. E., Thorsen, T. S., Kling, R. C., Granier, S., Gmeiner, P., Husbands, S. M., Traynor, J. R., Weis, W. I., Steyaert, J., Dror, R. O., and Kobilka, B. K. (2015) Structural insights into micro-opioid receptor activation. Nature 524 (7565), 315−21. (32) Fenalti, G., Giguere, P. M., Katritch, V., Huang, X. P., Thompson, A. A., Cherezov, V., Roth, B. L., and Stevens, R. C. (2014) Molecular control of delta-opioid receptor signalling. Nature 506 (7487), 191−6.
ASSOCIATED CONTENT
Special Issue Paper
Published as part of the special issue “DARK Classics in Chemical Neuroscience”.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: +91-571-2720388. Fax: + 91-571-2721776. ORCID
Rizwan Hasan Khan: 0000-0002-9965-8982 Present Address ∥
P.A.: Department of Biomedicine, Aarhus University, Aarhus C-8000, Denmark. Funding
For providing financial assistance M.K.S. and S.B. are thankful to Department of Biotechnology (DBT), New Delhi, India. P.A., A.E., and N.M. are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, India. R.H.K. is thankful to CSIR and UGC for project referenced as 37(1676)/17/EMR − II and F. 19-219/2018, respectively. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Facilities provided by Kusuma School of Biological Sciences, Indian Institute of Technology, HauzKhas, New Delhi, and Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh are gratefully acknowledged.
■
REFERENCES
(1) Salerian, A. J. (2016) Endorphin agonists for psychiatric disorders. Phys. Med. Rehabil. Res. 1 (3), 58−14. (2) Salerian, A. J. (2015) Endorphin agonists for severe depression. Pharm. Pharmacol. Int. J. 2 (2), 49−56. (3) Heymans, C. (1967) Pharmacology in old and modern medicine. Annu. Rev. Pharmacol. 7 (1), 1−15. (4) Park, R. H. R., and Park, M. P. (1990) Saint Vitus’ dance: vital misconceptions by Sydenham and Bruegel. J. R. Soc. Med. 83 (8), 512−515. (5) Lader, M. (1980) Benzodiazepines-The opium of the masses? In Commentaries in the Neurosciences, pp 609−615, Elsevier. (6) Ng, S. V. (2016) Opium Use in 19th-Century Britain: The Roots of Moralism in Shaping Drug Legislation. American Journal of Psychiatry Residents’ Journal 11 (6), 14−14. (7) Weber, M. M., and Emrich, H. M. (1988) Current and historical concepts of opiate treatment in psychiatric disorders. International clinical psychopharmacology 3 (3), 255−266. (8) Emrich, H. M., and Schmauss, C. (1991) Psychiatric aspects of opioid research. In Neurobiology of opioids, pp 363−367, Springer. (9) Alam, P., Chaturvedi, S. K., Siddiqi, M. K., Rajpoot, R. K., Ajmal, M. R., Zaman, M., and Khan, R. H. (2016) Vitamin k3 inhibits protein aggregation: implication in the treatment of amyloid diseases. Sci. Rep. 6, 26759. (10) Alam, P., Beg, A. Z., Siddiqi, M. K., Chaturvedi, S. K., Rajpoot, R. K., Ajmal, M. R., Zaman, M., Abdelhameed, A. S., and Khan, R. H. (2017) Ascorbic acid inhibits human insulin aggregation and protects against amyloid induced cytotoxicity. Arch. Biochem. Biophys. 621, 54−62. (11) Siddiqi, M. K., Alam, P., Chaturvedi, S. K., and Khan, R. H. (2016) Anti-amyloidogenic behavior and interaction of Diallylsulfide with Human Serum Albumin. Int. J. Biol. Macromol. 92, 1220−1228. (12) Siddiqi, M. K., Alam, P., Malik, S., Majid, N., Chaturvedi, S. K., Rajan, S., Ajmal, M. R., Khan, M. V., Uversky, V. N., and Khan, R. H. 187
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience (33) Thompson, A. A., Liu, W., Chun, E., Katritch, V., Wu, H., Vardy, E., Huang, X. P., Trapella, C., Guerrini, R., Calo, G., Roth, B. L., Cherezov, V., and Stevens, R. C. (2012) Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485 (7398), 395−9. (34) Felden, L., Walter, C., Harder, S., Treede, R. D., Kayser, H., Drover, D., Geisslinger, G., and Lotsch, J. (2011) Comparative clinical effects of hydromorphone and morphine: a meta-analysis. Br. J. Anaesth. 107 (3), 319−28. (35) Armstrong, S. C., and Cozza, K. L. (2003) Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II. Psychosomatics 44 (6), 515−20. (36) Inturrisi, C. E. (2002) Clinical pharmacology of opioids for pain. Clin J. Pain 18 (4 Suppl), S3−13. (37) Wermeling, D. P. (2015) Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Ther. Adv. Drug Saf. 6 (1), 20−31. (38) Chiang, C. N., and Hawks, R. L. (2003) Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend. 70 (2 Suppl), S39−47. (39) Helm, S., Trescot, A. M., Colson, J., Sehgal, N., and Silverman, S. (2008) Opioid antagonists, partial agonists, and agonists/ antagonists: the role of office-based detoxification. Pain Physician 11 (2), 225−35. (40) Pond, S. M., and Tozer, T. N. (1984) First-pass elimination. Basic concepts and clinical consequences. Clin. Pharmacokinet. 9 (1), 1−25. (41) Khroyan, T. V., Wu, J., Polgar, W. E., Cami-Kobeci, G., Fotaki, N., Husbands, S. M., and Toll, L. (2015) BU08073 a buprenorphine analogue with partial agonist activity at mu-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice. Br. J. Pharmacol. 172 (2), 668−80. (42) Elkader, A., and Sproule, B. (2005) Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin. Pharmacokinet. 44 (7), 661−80. (43) Threlkeld, T., Parran, T. V., Adelman, C. A., Grey, S. F., and Yu, Y. (2006) Tramadol versus buprenorphine for the management of acute heroin withdrawal: a retrospective matched cohort controlled study. Am. J. Addict. 15 (2), 186−191. (44) Commiskey, S., Fan, L. W., Ho, I. K., and Rockhold, R. W. (2005) Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J. Pharmacol. Sci. 98 (2), 109− 16. (45) Heel, R. C., Brogden, R. N., Speight, T. M., and Avery, G. S. (1978) Butorphanol: a review of its pharmacological properties and therapeutic efficacy. Drugs 16 (6), 473−505. (46) Dayer, P., Collart, L., and Desmeules, J. (1994) The pharmacology of tramadol. Drugs 47 (1), 3−7. (47) Miotto, K., Cho, A. K., Khalil, M. A., Blanco, K., Sasaki, J. D., and Rawson, R. (2017) Trends in tramadol: pharmacology, metabolism, and misuse. Anesth. Analg. 124 (1), 44−51. (48) Singh Balhara, Y. P., Parmar, A., and Sarkar, S. (2018) Use of tramadol for management of opioid use disorders: Rationale and recommendations. J. Neurosci. Rural Pract. 9 (3), 397. (49) Grond, S., and Sablotzki, A. (2004) Clinical pharmacology of tramadol. Clin. Pharmacokinet. 43 (13), 879−923. (50) Dunn, K. E., Tompkins, D. A., Bigelow, G. E., and Strain, E. C. (2017) Efficacy of tramadol extended-release for opioid withdrawal: a randomized clinical trial. JAMA psychiatry 74 (9), 885−893. (51) Kim, H.-C., Nabeshima, T., Jhoo, W.-K., Ko, K. H., Kim, W.-K., Shin, E.-J., Cho, M., and Lee, P. H. (2001) Anticonvulsant effects of new morphinan derivatives. Bioorg. Med. Chem. Lett. 11 (13), 1651− 1654. (52) Tortella, F. C., and Musacchio, J. M. (1986) Dextromethorphan and carbetapentane: centrally acting non-opioid antitussive agents with novel anticonvulsant properties. Brain Res. 383 (1−2), 314−318. (53) Zapata, A., Gasior, M., Geter-Douglass, B., Tortella, F. C., Newman, A. H., and Witkin, J. M. (2003) Attenuation of the
stimulant and convulsant effects of cocaine by 17-substituted-3hydroxy and 3-alkoxy derivatives of dextromethorphan. Pharmacol., Biochem. Behav. 74 (2), 313−323. (54) Choi, D. W. (1987) Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity. Brain Res. 403 (2), 333−336. (55) Zhang, W., Shin, E.-J., Wang, T., Lee, P. H., Pang, H., Wie, M.B., Kim, W.-K., Kim, S.-J., Huang, W.-H., Wang, Y., et al. (2006) 3Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. FASEB J. 20 (14), 2496−2511. (56) Zhang, W., Qin, L., Wang, T., Wei, S.-J., Gao, H.-m., Liu, J., Wilson, B., Liu, B., Zhang, W., Kim, H.-C., and Hong, J.-S. (2005) 3hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB J. 19 (3), 395−397. (57) Snyder, E. W., Shearer, D. E., Beck, E. C., and Dustman, R. E. (1980) Naloxone-induced electrographic seizures in the primate. Psychopharmacology 67 (3), 211−214. (58) Somera Molina, K. C., Robin, B., Somera, C. A., Anderson, C., Stine, C., Koh, S., Behanna, H. A., Van Eldik, L. J., Watterson, D. M., and Wainwright, M. S. (2007) Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Epilepsia 48 (9), 1785−1800. (59) Figuera-Losada, M., Rojas, C., and Slusher, B. S. (2014) Inhibition of microglia activation as a phenotypic assay in early drug discovery. J. Biomol. Screening 19 (1), 17−31. (60) Taylor, C. P., Traynelis, S. F., Siffert, J., Pope, L. E., and Matsumoto, R. R. (2016) Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol. Ther. 164, 170−182. (61) Ferkany, J. W., Borosky, S. A., Clissold, D. B., and Pontecorvo, M. J. (1988) Dextromethorphan inhibits NMDA-induced convulsions. Eur. J. Pharmacol. 151 (1), 151−154. (62) Shin, E.-J., Lee, P. H., Kim, H. J., Nabeshima, T., and Kim, H.C. (2008) Neuropsychotoxicity of abused drugs: potential of dextromethorphan and novel neuroprotective analogs of dextromethorphan with improved safety profiles in terms of abuse and neuroprotective effects. J. Pharmacol. Sci. 106 (1), 22−27. (63) Vezzani, A., Aronica, E., Mazarati, A., and Pittman, Q. J. (2013) Epilepsy and brain inflammation. Exp. Neurol. 244, 11−21. (64) Khurgel, M., Switzer Iii, R. C., Teskey, G. C., Spiller, A. E., Racine, R. J., and Ivy, G. O. (1995) Activation of astrocytes during epileptogenesis in the absence of neuronal degeneration. Neurobiol. Dis. 2 (1), 23−35. (65) Ravizza, T., Rizzi, M., Perego, C., Richichi, C., Veliskova, J., Moshe, S. L., De Simoni, M. G., and Vezzani, A. (2005) Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia 46, 113−117. (66) Marchi, N., Granata, T., and Janigro, D. (2014) Inflammatory pathways of seizure disorders. Trends Neurosci. 37 (2), 55−65. (67) Rizzi, M., Perego, C., Aliprandi, M., Richichi, C., Ravizza, T., Colella, D., Veliskova, J., Moshe, S. L., De Simoni, M. G., and Vezzani, A. (2003) Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol. Dis. 14 (3), 494−503. (68) Tufekci, K. U., Genc, S., and Genc, K. (2011) The endotoxininduced neuroinflammation model of Parkinson’s disease. Parkinson’s Dis. 2011, 1−25. (69) Smith, J. A., Das, A., Ray, S. K., and Banik, N. L. (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 87 (1), 10−20. (70) Hu, S., Sheng, W. S., Lokensgard, J. R., and Peterson, P. K. (2002) Morphine induces apoptosis of human microglia and neurons. Neuropharmacology 42 (6), 829−836. (71) Svensson, A.-L., Bucht, N., Hallberg, M., and Nyberg, F. (2008) Reversal of opiate-induced apoptosis by human recombinant growth hormone in murine foetus primary hippocampal neuronal cell cultures. Proc. Natl. Acad. Sci. U. S. A. 105, 7304. 188
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
Review
ACS Chemical Neuroscience (72) Pal, A., and Das, S. (2013) Chronic morphine exposure and its abstinence alters dendritic spine morphology and upregulates Shank1. Neurochem. Int. 62 (7), 956−964. (73) Carliss, R. D., Radovsky, A., Chengelis, C. P., O'Neill, T. P., and Shuey, D. L. (2007) Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain. NeuroToxicology 28 (4), 813−818.
189
DOI: 10.1021/acschemneuro.8b00546 ACS Chem. Neurosci. 2019, 10, 182−189
