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

Article  in  ACS Chemical Neuroscience · November 2018

DOI: 10.1021/acschemneuro.8b00546

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Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX 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

ABSTRACT: Opium has found great use medicinally for its analgesic properties and
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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
Downloaded via AARHUS UNIV on November 15, 2018 at 11:54:10 (UTC).

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 pharmaco-
logical 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
(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

© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.8b00546

ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience Review

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.

■ 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
B DOI: 10.1021/acschemneuro.8b00546
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-
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience Review

receptors are few of the novel but poorly characterized opioid

receptors. Initially considered to be an opioid receptor, the σ-
■ MEDICINAL CHEMISTRY AND PHARMACOLOGY
OF OPIUM
receptor is no longer classified with the opioid receptors As we have seen in Table 1, opioids can be classified as agonist,
because it displays neither the stereoselectivity characteristic of antagonist, partial agonist, or antagonist and mixed action.
opioid receptors nor antagonism by opioid antagonists.21
OPs are coupled to G proteins (G1 and G0), and they Table 1. Classification of Opioids
interact with these G proteins to inhibit adenylate cyclase, an
enzyme that promotes the formation of the intracellular source natural morphine, codeine
messenger cyclic adenosine 3′,5′-monophosphate (cyclic semisynthetic tramadol, heroin, oxycodone,
oxymorphone, and buprenorphine
AMP). G proteins also may mediate the inhibitory effects of synthetic entanyl, pethidine, and
opioids on voltage-gated calcium channels and their activating dextropropoxyphene
effects on inwardly rectifying potassium channels. Inhibition of chemical phenanthrenes morphine, codeine, heroin,
calcium channels may lead to a decrease in the release of structure hydromorphone, and oxycodone
neurotransmitters such as substance P, which mediates pain benzomorphans pentazocine and phenazocine
diphenylpropylamines propoxyphene, methadone, levo-Α-
signals.22 acetylmethadol, and loperamide
DOPs (agonist delta-alanine-delta-leucine-enkephalin) are phenylpiperidines meperidine
distributed throughout the central nervous system (CNS). anilidopiperidines fentanyl, alfentanil, and sufentanil
DOP density varies in different brain regions: the highest oripavine derivatives etorphine, dihydroetorphine, and
densities can be found in the olfactory bulb, neocortex, caudate buprenorphine
putamen, and nucleus accumbens, and to a lesser degree the morphinan derivatives levorphanol and butorphanol
thalamus, hypothalamus, and brain stem.20 This receptor is synthetic analogue of tramadol
codeine
involved in the antinociceptive/analgesic actions of some
function pure agonists morphine and codeine
opioids. Activation of DOP results in decreased presynaptic
partial agonists buprenorphine
Ca2+ influx, which inhibits release of neurotransmitters, and an mixed action pentazocine, nalbupine, and
increase in postsynaptic K+ efflux, which hyperpolarizes the butorphanol
neuron.23 antagonists naxolone
KOPs (agonist ketocyclazocine) are widely expressed
throughout the brain, spinal cord, and peripheral tissues. Their activity differs owing to their action on different opioid
They are responsible for spinal analgesia, sedation, dyspnea, receptors as well as genetic differences in opioid receptor
dependence, dysphoria, and respiratory depression. Activation sensitivity.24
of KOPs primarily leads to an inhibition of adenylyl cyclase Morphine, a classic example of a natural opioid, has agonistic
through the Gα subunit and induces increased potassium actions at the μ-, κ-, and δ-receptors.16 Being on the World
channel conductance and decreased calcium conductance via Health Organization (WHO) essential drugs list, it is widely
the Gβγ subunit. Modulation of these ion channels results in used as an analgesic commonly administered by different
decreased action potential generation and neurotransmitter routes such as intramuscular, intravenous, or oral. Major
release.24,25 features of morphine and morphine-like agonists in the CNS
MOP receptors are located throughout the central nervous include analgesia, drowsiness, euphoria, respiratory depression,
system including the cerebral cortex, amygdala (of the limbic nausea and vomiting, depressed cough reflex, and hypo-
system), and putamen of the basal ganglia (highest density).26 thermia.16,34 Morphine (285.34 g mol−1) has an oral
MORs modulate intracellular effectors through inhibitory Go/ bioavailability of 30%−75%, plasma elimination half-life of
Gi proteins as opioid agonists bind. In turn, receptor signaling 2−3.5 h, and octanol−water partition coefficient of 0.7.
is readily terminated by several cellular regulatory processes Morphine is chiefly metabolized through conjugation reactions
such as phosphorylation, desensitization, endocytosis, and with UGT2B7 (UDP-glucuronosyltransferase-2B7) enzyme,
downregulation.27 Antagonists like naloxone and naltrexone and hence, any genetic polymorphism of UGT2B7 may affect
block MOP, whereas agonists like methadone and buprenor- the action of morphine.35 The contributor of analgesic activity
phine partially activate the MOP.27 Major side effects of morphine is an active metabolite of the UGT2B7 pathway,
morphine-6-glucuronide (M-6-G). M-6-G is responsible for
associated with MOP agonists include respiratory depression,
sedation and nausea in patients with impaired renal excretory
while with MOP antagonist side effects such as peristalsis and
function (as it is excreted in the urine).34,36 A more water-
constipation are common. MOP opioids also have effects on soluble morphine metabolite (octanol−water partition coef-
the cardiovascular system, thermoregulation, hormone secre- ficient of 1.28), hydromorphone, is eight times more active
tion, and immune function.28 than morphine, and it does not have an active renally
The NOP receptor sequence is approximately 50−60% eliminated metabolite.16,34
identical to the classic opioid receptors.29 N/OFQ and its Naloxone (327.38 g mol−1) is a competitive μ-receptor
receptor are widely expressed throughout both the central and antagonist to opioids in the central nervous system. Naloxone
the peripheral nervous system.20 The N/OFQ (O, orphanin; F, also has been shown as an antagonist at other opioid receptors
phenylalanine; and Q, glutamine) peptide activates the NOP κ and δ but with a higher affinity for the μ receptor.24 Used as
receptor and triggers intracellular signaling events, including an antidote for opioid overdose, it has parenteral, intranasal,
inhibition of adenylyl cyclase and activation of various kinases pulmonary, or orotracheal intubation route of administration.37
like protein kinase C (PKC) and p38 mitogen-activated Naloxone is a potent inhibitor of the UGT2B7 pathway and
protein kinase and modulation of calcium and potassium thereby reduces the effect of morphine by altering M-6-G
channel conductance.29 production; however, naloxone has no effect if opioids are not
C DOI: 10.1021/acschemneuro.8b00546
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
present in a person.24 In naloxone postoperative patients,
various adverse effects include cardiac disorders, gastro-
intestinal 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 bupre-
norphine (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 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 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 metabo-
lized 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-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, 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 with-
drawal symptoms.50
■
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
D DOI: 10.1021/acschemneuro.8b00546
Review
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 nootropic effect
derivatives
DM
analogues
DM and DX have anticonvulsant effects that suppress seizures
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-17-
methylmorphinan) 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 anticonvul-
sive and proconvulsive actions have been reported for the σ-
receptor 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
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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 endotoxin-
induced 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 neuron-
enriched cultures. 3-HM was neuroprotective against endotox-
in-induced dopamine (DA) neurotoxicity and also to DA
neurons in primary mixed mesencephalic neuro-glial cul-
tures.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, 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
activation.55
Several investigations for the neuroprotective property of
analogues of dextromethorphan (DM) in endotoxin-lip-
opolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (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 S-
100β 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
E DOI: 10.1021/acschemneuro.8b00546
Review
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 treat-
ment 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). Hyper-
locomotor 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 neuro-
protection. 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.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
■ ASSOCIATED CONTENT
Special Issue Paper
Published as part of the special issue “DARK Classics in
Chemical Neuroscience”.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: rizwanhkhan1@gmail.com. Phone: +91-571-2720388.
Fax: + 91-571-2721776.
ORCID
Rizwan Hasan Khan: 0000-0002-9965-8982
Present Address
∥ Biophysical insight into the anti-amyloidogenic behavior of taurine.
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 Uni-
versity, Aligarh are gratefully acknowledged.
■
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H DOI: 10.1021/acschemneuro.8b00546
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX

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