DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe

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DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe Parvez Alam, Subhomoi Borkotoky, Mohammad Khursheed Siddiqi, Aquib Ehtram, Nabeela Majid, Moin Uddin, and Rizwan Hasan KHAN ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00546 • Publication Date (Web): 07 Nov 2018 Downloaded from http://pubs.acs.org on November 7, 2018

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ACS Chemical Neuroscience

DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe Parvez Alam1,4, Subhomoi Borkokoty1, Mohammad Khursheed Siddiqi2, Aquib Ehtram1, Nabeela Majid2, Moin Uddin3and Rizwan Hasan Khan2,*

1Kusuma

School of Biological Sciences, Indian Institute of Technology, Hauz Khas, New Delhi, India 2Interdisciplinary

Biotechnology Unit, Aligarh Muslim University, Aligarh, India

3Department

of IlmulAdvia (Unani Pharmacology), Ajmal Khan Tibbiya College, Aligarh Muslim University, Aligarh, India 4Present

address: Department of Biomedicine, Aarhus University, Aarhus C- 8000, Denmark

*To whom correspondence should be addressed: Prof. Rizwan Hasan Khan, PhD, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh-202002, U.P., India. E-mail: [email protected]; Phone: +91-571-2720388; Fax: + 91-5712721776

Key words: Opium, neuroscience, neurodegeneration, medicine, mechanism

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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 efficacious for relieving pain and the treatment of epileptic seizures, but the progressive research towards their use in the treatment of neurodegenerative diseases remain elusive. For getting more insight of the other properties of opium like anti-inflammatory, herein we will be discussing the basic information regarding opium, opium content and their mechanism of action, pharmacology of opium derivatives, role of opium in the prevention of neurodegeneration and adverse effects of opium derivatives on the neuronal health.


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Introduction Opium is the dried latex obtained from the opium poppy. Opium latex contains morphine, codeine, thebaine, papaverine and noscapine etc. (Figure 1). Since prehistoric time opiates are being used for, medicinal purposes including relieving pain in cancer, spasms from tetanus, and pain attendant to menstruation and childbirth. The plant papaver has been known for its medicinal benefits as it alsoseveral 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 actively since approximately 3400 BCE.

The oldest archeological

occurrence of poppy species was documented for the wild poppy, Papaver setigerum (P. 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 the patients of malaria for relieving pain 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 non-addicting cough suppressant which was 5 to 10 times as 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 Dioscurides1st century and Galen [129- 199] have referred to the narcotic analgesic properties of opium1. And it was Paracelcus [1493- 1541] a Swiss German alchemist who observed that certain analgesic opium alkaloids are far more soluble in alcohol then 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 mania4. Then, in general the 18th century witnessed opium as one of the more popular medications used in psychiatry5-7. In 1991, Weber and Emrich published an extraordinary review of opiate treatment in psychiatric disorders8.

Figure 1: Structures of most common opium alkaloids. Previously our group has report the effect of small molecules in preventing amyloid formation in proteins and their ability to protectneuronal cells against amyloid induced cytotoxicity.9-15 In this review, we discussed about some basic information regarding opium, opium content and their mechanism of action, pharmacology of opium derivatives, role of opium in prevention of neurodegeneration and adverse effect of opium derivatives on the neuronal health and will attempt to widely dispersed data into one easily accessible format for the “Classics in Chemical Neuroscience” series.


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Opium content and Mechanism of action Opium contains both non-alkaloid and alkaloid constituents. The non-alkaloid 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 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 receptor (OP) 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 non-classical i.e. nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). NOP shares significant sequence homology with the classical opioid receptors 20. The ɛ, ι, λ and ζ-receptors are few of the novel but poorly characterized opioid receptors. Initially considered to be an opioid receptor, the σ-receptor is no longer classified with the opioid receptors it displays neither the stereoselectivity characteristic of opioid receptors nor antagonism by opioid antagonists 21.



Table1: Classification of opioids

Source

Natural

Morphine, Codeine

Semi-synthetic

Tramadol, Heroin, Oxycodone, Oxymorphone, and Buprenorphine

Synthetic

Entanyl, Pethidine, and Dextropropoxyphene

Phenanthrenes

Morphine, Codeine, Heroin, Hydromorphone, and Oxycodone.

Benzomorphans

Pentazocine and Phenazocine

Diphenylpropylamines

Propoxyphene, Methadone, Levo-Α-

Chemical Structure

Acetylmethadol, and Loperamide Phenylpiperidines

Meperidine

Anilidopiperidines

Fentanyl, Alfentanil, and Sufentanil

Oripavine derivatives

Etorphine, Dihydroetorphine, and Buprenorphine

Morphinan derivatives

Levorphanol and Butorphanol

Synthetic analogue of

Tramadol

codeine

Function

Pure agonists

Morphine and Codeine

Partial agonists

Buprenorphine

Mixed action

Pentazocine , Nalbupine and Butorphanol

Antagonists

Naxolone

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


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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 signals22. DOPs (agonist delta-alanine-delta-leucine-enkephalin) are distributed throughout the central nervous system (CNS). DOP density varies in different brain regions: highest densities can be found in the olfactory bulb, neocortex, caudate putamen and nucleus accumbens, and to a lesser degree the thalamus, hypothalamus and brainstem20. 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), 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 down-regulation

27.

Antagonists like

naloxone and naltrexone block whereas agonists like methadone and buprenorphine partially activate the MOP

27.

Major side-effects associated with MOP agonists include respiratory



depression, while with MOP antagonists 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 conductance29.

Figure 2. The 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 nervous system.


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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. Their activity differs owing to their action on different opioid receptors as well as genetic differences in opioid receptor sensitivity24. Morphine, a classic example of natural opioid, has agonistic actions at the µ, κ, and δ receptors 16.

Being on WHO’s (World health organization) essential drugs list, it is widely used as

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 hours and octanol-water partition coefficient of 0.7. Morphine is chiefly

metabolized

through

conjugation

reactions

with

UGT2B7

(UDP-

Glucuronosyltransferase-2B7) enzyme, 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 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 water soluble 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 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 UGT2B7 pathway, thereby reduces the effect of morphine by altering



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M-6-G production, however, naloxone has no effect if opioids are not 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, vascular disorders etc37. Naloxone is metabolized in the liver and primarily undergoes glucuronidation to form naloxone-3-glucuronide and excreted through urine (24%- 37% ) is excreted as metabolites within first 6 hours) 38. Naloxone has low oral bioavailability (~2%) due to extensive first-pass metabolism 39, 40. The mixed agonist-antagonists and partial agonist buprenorphine ( 467.64

gmol-1)

is

a

semisynthetic opioid, has a poor bioavailability with extensive first pass effect by the liver but has an excellent sublingual bioavailability due to high lipid solubility

16, 39.

This potent

analgesic is a high-affinity partial μ receptor 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, hence 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 man, mainly to


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hydroxybutorphanol. Butorphanol is excreted through the urinary (about 70%) and biliary (about 11 to 14%) mode of elimination. Adverse effects include sedation, nausea, respiratory depression and psychotomimetic reactions 45. Tramadol (263.381 g mol-1), a synthetic 4-phenyl-piperidine 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 includes 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 also seen as a useful agent in the management of heroin withdrawal43. The extended-release (ER) formulation of tramadol is more effective than clonidine and comparable to buprenorphine in reducing opioid withdrawal symptoms50. Nootropism of opium derivatives Nootropic is a term used for the exploitation of the medications or wholesome supplements that positively affect brain function. Various pharmaceutical compounds are available in the market, which has been exploited for their neuroprotective property by altering specific neurotransmitters or opioid receptors binding. Several opium derivatives have been found to play roles in attenuating the neurodegeneration. Nootropic roles of opium derivatives are presented in table 2 and discussed thereafter in details. Table 2: Opium derivatives and their nootropic effect Opium Derivatives DM analogs

Nootropic Effect DM and DX have anticonvulsant effects that suppress seizures induced by electroshock.51-53



3-HM

NALOXONE

DM prevents seizures, mortality and hippocampal cell loss in a dose-dependent manner.54 DM minimizes the toxicity of the glutamate on the neuronal cells.54 DX attenuates both morphological and chemical evidence of glutamate neurotoxicity in murine neocortical cell cultures.54 Neuroprotective against endotoxin-induced DA neurotoxicity.55 Nootropic to DA neurons in primary mixed mesencephalic neuro-glial cultures.56 Caused the release of certain nootropic factors (i.e., EGF, GDNF, TGF-β1, TGFα1, and ADNF) from astroglia, exerting nootropic effect on DA neurons.55 Most potent in restoring DA neuronal loss and DA depletion as well as in attenuating behavioral damage.55 Increases the levels of nootropic factors and decreases the production of reactive oxygen species in LPS and MPTP PD models.55 Attenuate microglial activation in a dose-dependent manner.57 Attenuates cytokines that block the astrocyte activation, decreasing the brain vulnerability to epilepsy.58 Inhibits microglia driven neural-inflammation.59

DM analogues Opium derivatives have also been found to be involved in the treatment of epileptic seizures known as anticonvulsants. Dextromethorphan (DM; 3-methoxy-17-methylmorphinan) and its metabolitedextrorphan (DX) have been reported to have anticonvulsant effects that suppress seizures induced byelectroshock51-53. Most studies confirm that DX is several times more potent than DM as an anticonvulsant51. This may be due to the in- vivo conversion of the DM to DX significantly contributing towards the anticonvulsant activity of the parent molecule. Both molecules show an affinity towards sigma receptors, the binding that is responsible for the anticonvulsant properties. DM have 2-5 folds higher affinity than DX, whereas the anticonvulsant property of DX is higher than DM60. Thus the mechanism underlying the anticonvulsant effect remains undetermined. Both anticonvulsive and proconvulsive actions have been reported for the sigma receptor binding that is responsible for the neuroprotective behaviour51.


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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 receptors54. DM manages to inhibit NMDA receptor by acquiring a non-competitive antagonist site of the receptor. On the contrary, DX is a more potent ligand towards noncompetitive antagonist site of the NMDA receptor and is constant with the anticonvulsant effects in-vivo54, 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 cultures54 3-HM Progressive research for the development of effective therapeutics against neurodegeneration is limited. A structural analog of DM, 3-HM which lacks methyl groups at O and N sites showed prominent results in the treatment of PD and showed the neuroprotective properties amongst the DM analogs available55. Studies showed that 3-HM was more potent in restoring neuroprotection against endotoxin-induced neurotoxicity than DM, its parent molecule56. The nootropic effect of 3-HM was specifically glial dependent, and 3-HM failed to restore any protective impact in neuron-enriched cultures. 3-HM was neuroprotective against endotoxininduced DA neurotoxicity and also to DA neurons in primary mixed mesencephalic neuro-glial cultures55, 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 PD55. One potential therapeutic intervention will be to stimulate astroglia to produce these nootropic factors to rescue damaged neurons55. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of endotoxin-induced production of an array of pro-inflammatory and neurotoxic factors. Thus, 3-HM provides neuroprotection by acting on two different cell targets: a nootropic effect mediated by astroglia and an anti-inflammatory effect mediated by inhibition of microglial activation55. Several investigations for the neuroprotective property of analogs of dextromethorphan (DM) in endotoxin-lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to classify neuroprotective drugs for Parkinson's disease (PD) have been done55. In vivo studies on the two models showed that daily doses of DM metabolite protected dopamine (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 behavioural damage. By increasing the gene expression of variousnootropic factors, and decreasing the production of ROS (reactive oxygen species), 3HM showed the neuroprotective properties in LPS and MPTP PD models55, 62. Due to its high efficacy and low toxicity, 3-HM could be a novel therapy for PD. Naloxone Role of inflammation has been long established in the groups of epileptic neurological disorders63. 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 epileptogenesis64, 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 injury66. Status Epilepticus (SE) induced cytokine


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production in postnatal day 15 (PN 15) was studied, where IL-1β and S-100β levels were found to be strongly alleviated58,

67.

Naloxone, a potential opioid receptor antagonist has been

investigated to attenuate microglial activation in a dose-dependent manner57. The studies suggested PN15 SE induced glial derived IL-1β and S-100β could be minimized when given in optimal doses58. Naloxone driven attenuation of cytokines blocks the astrocyte activation thereby decreasing the brain vulnerability to epilepsy58. Endotoxin driven inflammation leads to the activation of microglia, which in turn produces pro-inflammatory cytokines and neurotoxic factors, such as TNF-α, NO, IL-10, superoxide and free radicals which subsequently mediates dopaminergic neurodegeneration68. Naloxone has been shown to be a neuroprotective agent through the inhibition of microglia driven neuralinflammation59. The underlying mechanism lies with the inhibition of cytokines and neurotoxic factors from activated microglial cells69. 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 induces apoptosis in both neurons and microglial cells70. The cytotoxicity of morphine has been found to be dose-dependent where asingle dose of morphine did not induce apoptosis but the administration of large morphine doses induced apoptosis in neuronal cells70, 71. The morphological studies showed that chronic morphine treatment leading 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 the 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 behavioural depression is demonstrated when these offspring received additional DM51, 62. Pathological damage in the posterior cingulate cortex and retrosplenial cortex of the rat brain has been reported with a single treatment with non-competitive 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 acts as potential agents towards neuroprotection. In this review as the mechanism of their action has been evaluated which supports the idea that opium derivatives upon binding to their respective receptors causes the decreased influx of calcium which can be exploited for the treatment of neurodegenerative diseases like Alzheimer’s, Parkinson’s, etc. 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 protofibrills into mature amyloid fibrils. Despite their negative effects on over dosage that are comparatively less than their beneficial effects they can be included by the pharmacists in the formulation of anti- aggregating drugs for the treatment of various neurodegenerative diseases. There is urgently need to design the drug molecules based on opium contents and their neuro protective potential must be explored in animal models in order to get better therapy for neurodegenerative diseases in future. Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.


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Acknowledgements 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. 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. 19219/2018, respectively. REFERENCES 1. Salerian, A. J., Endorphin agonists for psychiatric disorders. Physical Medicine and Rehabilitation Research 2016, 1, (3), 58-14. 2. Salerian, A. J., Endorphin agonists for severe depression. Pharmacy and Pharmacology International Journal 2015, 2, (2). 3. Heymans, C., Pharmacology in old and modern medicine. Annual review of pharmacology 1967, 7, (1), 1-15. 4. Park, R. H. R.; Park, M. P., Saint Vitus' dance: vital misconceptions by Sydenham and Bruegel. Journal of the Royal Society of Medicine 1990, 83, (8), 512-515. 5. Lader, M., Benzodiazepines-he opium of the masses? In Commentaries in the Neurosciences, Elsevier: 1980; pp 609-615. 6. Ng, S. V., Opium Use in 19th-Century Britain: The Roots of Moralism in Shaping Drug Legislation. American Journal of Psychiatry Residents' Journal 2016, 11, (06), 14-14. 7. Weber, M. M.; Emrich, H. M., Current and historical concepts of opiate treatment in psychiatric disorders. International clinical psychopharmacology 1988, 3, (3), 255-266. 8. Emrich, H. M.; Schmauss, C., Psychiatric aspects of opioid research. In Neurobiology of opioids, Springer: 1991; pp 363-367. 9. Alam, P.; Chaturvedi, S. K.; Siddiqi, M. K.; Rajpoot, R. K.; Ajmal, M. R.; Zaman, M.; Khan, R. H., Vitamin k3 inhibits protein aggregation: implication in the treatment of amyloid diseases. Scientific reports 2016, 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.; Khan, R. H., Ascorbic acid inhibits human insulin aggregation and protects against amyloid induced cytotoxicity. Archives of Biochemistry and Biophysics 2017, 621, 54-62. 11. Siddiqi, M. K.; Alam, P.; Chaturvedi, S. K.; Khan, R. H., Anti-amyloidogenic behavior and interaction of Diallylsulfide with Human Serum Albumin. International Journal of Biological Macromolecules 2016, 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.; Khan, R. H., Stabilizing proteins to prevent conformational changes required for amyloid fibril formation. Journal of cellular biochemistry 2018.



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GRAPHICAL ABSTRACT

DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe Parvez Alam1,4, Subhomoi Borkokoty1, Mohammad Khursheed Siddiqi2, Aquib Ehtram1, Nabeela Majid2, Moin Uddin3and Rizwan Hasan Khan2,*


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DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe

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