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Home , DADLE, TRIMU 5

Vol 7|Issue 2| 2017 |61-67.

Asian Journal of Pharmaceutical Science & Technology

e-ISSN: 2248 – 9185 www.ajpst.com Print ISSN: 2248 – 9177

OPIOID RECEPTORS: AN OVERVIEW

Priyanka P. Pawar*1, Kundan J. Tiwari2, Supriya T. Garud2, Manjula T. Ruparel2

1S.M.B.T. College of Pharmacy, Nandi-hills Dhamangaon, Nashik, India. 2S.M.B.T. Institute of D Pharmacy, Nandi-hills Dhamangaon, Nashik, India.

ABSTRACT drugs play important roles in the clinical management of pain were Opioid receptors have been targeted for the treatment of pain. Opioid receptors are widely involve in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. The opioid receptors involved in the spinal action of for production and/or modulation of analgesia. The two approaches were used as supraspinal and spinal sites. The mu (µ), kappa(k), delta(δ), opioid receptors represent the originally classified receptor subtypes with like -1 (ORL) being the least characterized. All four receptors are G-protein coupled receptor and activate inhibitory G- proteins.

Key words: Receptor, Pain, Epilepsy, Seizures, Supraspinal.

INTRODUCTION Receptors are proteins which are, by far, the most . Partial agonist –An agent which activates a receptor important drug targets in medicine. They are implicated in to produced submaximal effect but antagonizes the action of ailment such as pain, depression, Parkinson diseases. full agonist. Receptors identified by specific neurotransmitter or by Antagonist – An agent which prevents the action of an agent hormone which activates them. Thus receptor activated by on receptor or the subsequent response but does not have dopamine is called as dopaminergic receptors, the receptor any effect of its own. activated by acetylcholine is called as cholinergic receptor, Ligand – Any molecules which is attached selectively to and receptor activated by adrenergic receptor is called as particular receptors. adrenaline receptor [1]. The interaction of drug with receptor was and other exert their actions by analogous a “lock” and “key”. Thus, certain organic interacting with specific receptors present on neurons in the compounds would fit properly into the receptor and activate CNS and in peripheral tissues. Chemical modification of it, leading to a high degree of specificity. morphine structure has yielded a number of compounds The term refers to that which have a complex pattern of morphine-like and other are structurally related to morphine, whereas opioids is term agonistic and antagonistic actions that cannot be explained used to cover all the synthetic, semisynthetic, naturally on the basis of a single opioid receptor. Radioligand binding occuring, and endogenous compounds that interact with studies have divided the opioid receptors into three types (μ, opioid receptors in the body. It is important to appreciate k, δ); which have been cloned. Each has a specific that the opioids are not only compounds which are of use in pharmacological profile and pattern of anatomical the relief of pain: there are several other classes of distribution in the brain, spinal cord and peripheral tissues , including aspirin. [1-3]. The use of terms and opioid requires some The following term are used in describing drug receptor clarification. In addition to having pharmacologic effects interaction: similar to morphine, a compound must be antagonized by an Agonist – An agent who activates a receptor to produce an such as to be classified an opioid effect similar to that of physiological signal molecules. [1-3]. Inverse agonist – An agent who activates a receptor to Opioid ligands can interact with different opioid produce an effect in the opposite direction to that of the receptors as , partial agonists or competitive

Corresponding Author: Priyanka P. Pawar E-mail: [email protected] 61 | P a g e

Vol 7|Issue 2| 2017 |61-67. antagonists. The overall pattern of effect a particular agent Type A):- Mu (µ) Receptors [Mu for morphine] MOR depends not only on the nature of its interaction with The mu receptors are found primarily in the different opioid receptors, but also on its relative affinity for brainstem and medial thalamus. The mu receptors is these, example:- morphine is an agonist on mu, kappa, delta characterized by its high affinity for morphine. The receptors, but its affinity for mu receptor is much higher endogenous ligand for mu receptors-peptides called than that for other two. The effects, therefore, are primary 1 and 2, have only recently been found in the result of mu receptor activation [2, 3]. mammalian brain. They produce biological effects ascribed The opioid receptors belong to family of G-protein to mu receptor. Other opioid peptides viz. β-endorphin, coupled receptor. The opioid receptors distributed , and bind to mu receptors with throughout the brain, spinal cord, and peripheral tissues. lower affinity [1]. The study of the biological functions of opioid receptors in- -1 (Tyr-Pro-Trp-Phe-NH2) and vivo was aided by the synthesis of selective antagonists and endomorphin -2 (Tyr-Pro-Phe-NH2) are endogenous opioid agonist. In-vivo infusion of selective antagonists and peptide with high degree of selectivity for mu receptors. In agonists were used to establish the receptor types involved general agonist at mu receptors produce analgesia, in mediating various opioid effects. respiratory depression, decreased gastro-intestinal motility, The morphine activates analgesic receptors in the euphoria, feeding and release of hormone. Most clinically central nervous system (CNS) and that this leads to a used opioid drugs bind to the mu receptors. The opioid reduction in the transmission of pain signal to the brain [3]. drugs bind to the mu receptors. The opioid drugs is The morphine act agonist at all three types of morphine, codein, , , , receptor (mu, kappa, and delta) and activation leads to a . variety of cellular effect depending on the type of receptor Activation of mu receptors by an agonist causes involved. These include the opening of potassium ion itching, nausea, slightly reduced blood pressure, miosis, channels, the closing of calcium ion channel, or the decreased bowel motility often leading to constipation. The inhibition of neurotransmitter release. overdose of opioids kills through apnea and fatal hypoxia, Activation of all three types of opioid receptors often caused by combination with alcohol, benzodiazepines (Mu, Kappa, and Delta) can produce antinociception, but or barbiturates. Opioid overdoses can be rapidly reversed there are significant differences in the effects of activating through the use of opioid antagonist that is the naloxone is different receptor types, depending on noxious stimulus use [1, 4]. used. A variety of antinociceptive assays that used different The mu receptors also found in intestinal tract noxious stimuli and different animal species have been used which cause constipation. The mu receptors exist either pre- to examine the activity of potential analgesics. Animal synaptically or post-synaptically depending upon cell type. model for pain include models of acute pain (example- hot The mu receptors have high affinity for enkephalins and β- plate, tail flick, paw pressure, and writhing assays), endorphin but low affinity for dynorphins. Naloxone, persistent pain (example:- the formalin test), chronic pain , , , are the (example:- adjuvant induced arthritis) and neuropathic antagonist involved in mu receptors while Fentanyl, pain (example:- nerve ligation) Endorphin, Methadone, Pentazocine, Enkephalin, , Morphine, , are TYPES OF OPIOID RECEPTORS agonist involved in kappa receptors. The opioid receptors are activated by morphine. Two subtypes of mu receptors have been proposed:- The opioid receptors are mainly classified as three types 1) Mu1 (µ1) receptor A) Mu (µ) receptors (Mu for morphine) : MOR 2) Mu2 (µ2) receptor 1) Mu1 (µ1) receptor 2) Mu2 (µ2) receptor Mu1 (µ1) receptor B) Kappa () receptors (Kappa for ketocyclazocine) : The mu1 receptor has higher affinity for morphine, KOR mediates supraspinal analgesia and is selectively blocked by 1) Kappa1 (1) receptor . Generally the mu1 receptor located in brain. 2) Kappa3 (3) receptor The function of mu1 receptor is analgesia and physical C) Delta () receptor (Delta for deferens) : “DOR” dependence. The selective agonist of mu1 receptor containing and . 1) Delta1 (1) receptor 2) Delta2 (2) receptor The fourth type of opioid receptors have been later Mu2 (µ2) receptor identified in the 1990s which shows a lot of structural The mu2 receptor have lower affinity for similarity to the classical opioid receptors morphine, mediates spinal analgesia, respiratory depression D) Nociception / Orphan receptor : NOR and constipation action. Generally mu2receptor located in cortex (laminae 3 and 4). The function of mu2 receptor is

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Vol 7|Issue 2| 2017 |61-67. miosis, euphoria, reduced gastrointestinal motility, and The delta receptors have high affinity. The physical dependence. activation of delta receptors produces some analgesia. Delta receptors are present in dorsal horn of spinal cord. The Type B):- kappa () receptors [kappa for limbic areas are rich in delta receptors. The proconvulsant ketocyclazocine] KOR action is more prominent in delta agonist. In delta receptors The kappa receptor defined by its high affinity for the endomorphin have less selective. The non-peptide ketocyclazocine and A. The kappa receptor is a agonists and antagonist have been design to study the protein. The kappa receptors are primarily found in limbic, function of delta receptors. Generally Etorphine, brainstem, and spinal cord. The kappa receptor binds to Enkephalin, Cyclazocin, levorphinol, Endorphine, dynorphin as primary endogenous ligand. In Deltorphine are the agonist involved in delta receptors addition to dynorphin, a variety of natural alkaloids and while the Naltrexone, Naltrindol, and Naltrexone are the synthetic ligands binds to receptor. The kappa receptors antagonist involved in the delta receptors [1]. may provide a natural addiction control mechanism, and Naltrindol penetrate the CNS and displays therefore the drug that act as agonists and increase antagonist activity that is selective for delta receptors in- activation of this receptor may have therapeutic potential in vitro, and in-vivo systems. Delta receptors antagonist have the treatment of addiction [1]. been shown critical potential as immunosuppressants [4]. and are two The delta receptors have less serious side effects as compounds used in early studies to investigate kappa compare to mu receptors, for example:- The delta receptors receptors. They are not highly selectivity kappa agonist does not cause sedation, euphoria, or physical dependence. generally produce analgesia, other effects are respiratory Delta receptors have been produce respiratory depression, depression (lower ceilling) dysphoria, psychomimetics, gastrointestinal motility, affective behaviour and miosis, sedation, and reduced gastrointestinal motility. proconvulsants etc [1]. The kappa receptors are also known for their characteristic diuretic effects, due to their negative Subtypes of Delta receptors regulation of antidiuretic hormone (ADH). The kappa Two subtypes of delta receptors have been proposed receptors activation by agonist is coupled to the G-protein 1) Delta1 (1) receptor Gi/Go, which subsequently increases phosphodiaesterase 2) Delta2 (2) receptor activity. The kappa receptors have been shown to interact with sodium-hydrogen antiporter 3 regulators [1, 4]. Delta1 (1) receptor The Endomorphine-1 and Morphine are less The delta1 (1) receptor located in brain. The selective in kappa receptors. Generally Pentazocine, delta1 receptor produces the analgesia and antidepressant Etorphine, , , and effects. Levorphanol are agonist involved in kappa receptors while Naloxone, Naltrexone, Buprenorphine, Diprenorphine, Nor- Delta2 (2) receptor (Nor-BNI) these are the antagonist The delta2 (2) receptor located in amygdala involved in kappa receptors. olfactory bulbs, deep cortex, peripheral neurons etc. The delta2 receptor produces convulsant effects and physical Subtypes of Kappa receptors dependence. Two subtypes of kappa receptors have been proposed:- 1) Kappa1(1) receptor Type D):- Nociception /Orphan Receptors NOR 2) Kappa3(3) receptor The orphan receptors as its endogenous ligand is not known, but endogenous ligand have been identified as Kappa1 (1) receptor polypeptide structure called nociception. The kappa1 (1) receptor have mediates analgesia. The activation of orphan receptors can either Generally the kappa1 receptor located in brain. increase or decrease the sensitivity to pain depending on the location of receptor and the method by which agonists are Kappa3 (3) receptor administered. The orphan receptors are located in brain, The kappa3 (3) receptor have mediates the lower cortex, spinal cord, amygdale hypothalamus. The function ceiling supraspinal analgesia. Generally the kappa3 receptor of orphan receptors is anxiety, and depression. located in spinal cord, peripheral sensory neurons. The function of kappa3 receptor is diuresis, dysphoria, miosis, Physiology and pharmacology of opioid receptors neuroprotection, sedation, and stress etc. A) Opioid effects in the central nervous system and the periphery Type C):- Delta () Receptors [Delta for deferens] DOR B) Multiple opioid receptor types:-

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 Discovery of multiple opioid receptor types current related ORL1 receptor. This nomenclature have not gained nomenclature widespread acceptance, however, and in 2000 the  Signal transduction mechanisms “International Narcotic Research Conference”  Characterization of opioid receptors recommended a modified nomenclature DOP, KOP, MOP, and NOP for δ, k, µ and ORL1 receptors, respectively, Opioid effect in the central nervous system and which is consistent with the nomenclature requirements of periphery “IUPHAR”. Opioid receptors are found in the both CNS and in periphery. In the CNS different types of opioid receptors (µ, Signal transduction mechanism Ƙ, ɗ receptors); exhibit distinct anatomical distributions, There is considerable evidence that opioid and there is considerable species variation in both relative receptors are coupled to G-proteins and produce their density and receptor distribution. Peripheral receptors effects through these proteins. The structure of cloned mediate some effects of opioids, such as inhibition of gut opioid receptors is consistent with their belonging to this motility, and for a number of years receptors from tissues receptor superfamily. G-proteins are heterotrimers, such as the guinea pig ileum (GPI) formed the basis of consisting of α, β, γ subunits, which bind guanine standard bioassays used to assess compounds for opioid nucleotides to their α-subunit and catalyze the hydrolysis of activity. Peripheral receptors have also been implicated in GTP to GDP. G-protein mediate the interaction of opioid analgesia, particularly in cases of inflammation [5-7]. and other receptors with a variety of effector system, including adenylyl cyclase and ion channels. Multiple opioid receptors types The effector systems that have been implicated in 1) Discovery of multiple opioid receptors types and the transduction mechanisms for opioid receptors, the best current nomenclature studies is opioid inhibition of adenyl cyclase. Thus binding 2) Signal transduction mechanisms of an agonist to opioid receptors inhibits the activity of 3) Characteristic of opioid receptors adenylyl cyclase and decrease intracellular cAMP in a number of different tissues. Agonist activation of all three Discovery of multiple opioid receptors types and current types of cloned opioid receptors to inhibit adenyl cyclase nomenclature have been demonstrated. There is also some evidence that µ Our understanding of Opioid receptors has and k opioid receptors can stimulate adenylyl cyclase in expanded considerably from the early assumption of a certain tissues. There are conflicting receptors on whether δ single opioid binding site to the characterization of multiple opioid receptors stimulate or inhibit phosphatidylinsterol types of opioid receptors. The initial proposal of opioid turnover in some tissues; δ and µ receptors however, do not receptors by Beckett and Casy in 1954 assumed a single appear to be coupled to phosphatidylinositol turnover in opioid binding site. Multiple opioid receptors were neuroblastoma cell lines [5-7]. postulated as early the 1960s by both Portoghese (82) and Opioid receptors can also be coupled to ion Martin (83). On the basis of the pharmacological profile of channels through G-proteins. All three receptor types can variety of opioids, Martin proposed three types of opioid decrease voltage-dependent Ca++ current. The coupling of receptors, µ, k, and δ receptors, with morphine, opioid receptors to calcium channels involves a G-protein, ketocyclazocine, and SKF-10,047 respectively, as the and the actions of opioids on Ca++ current are blocked by prototypical ligands. The discovery of the enkephalins led to pertussis toxin, indicating involvement of Gi or Go. proposal of distinct opioid receptors type, the µ receptor, for Activation of µ and k receptors can also increase K++ these opioid peptides. The existence of three distinct opioid conductance. Similar to results found for calcium channels, receptor types, the µ, k, and δ receptors, have now been potassium channel coupling to opioid receptors appears to clearly established and these receptors have been cloned. involve a G-protein and is sensitive to pertussis toxin. Sigma receptors, however, are not considered opioid Agonist binding to opioid receptors also appears to receptors because effects associated with this receptor are activate the the extracellular signal regulated kinase (ERK) not reversed by opioid antagonist such as naloxone. Other cascade. opioid receptor types have also been proposed but this receptor types are not universally accepted. Although Characterization of opioid receptors distinctly different from opioid receptors, the ORL1 Early evaluation of compounds for opioid activity receptor interacts with the opioid receptors system in relied on testing for antinociceptive activity in vivo. These regulation of analgesia and other physiological effects [5-7]. pharmacological assays are often predictive of analgesic In 1996 the “International Union of Pharmacology” activity in humans, but the activity of compounds observed (IUPHAR) recommended that OP1, OP2, OP3 be used as in these assays is affected by a variety of factors, including the accepted names for δ, k, µ receptors, respectively, to the route of administration of the compound, the ability of replace the DOR, KOR, and MOR nomenclature typically compound to cross the blood brain-barrier into the CNS, the used in the literature; OP4 have been proposed name for the susceptibility of the compound to metabolism and

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Vol 7|Issue 2| 2017 |61-67. pharmacokinetics, the choice of noxious stimulus, and the Kappa (Ƙ), delta (ɗ) have been cloned; all are GPCRs animal species and strain used for assay. The results of in located mostly on prejunctional neurones. They generally vitro assays are not influenced by many of these factors that exercise inhibitory modulation by decreasing release of the complicate in vivo assays. The pharmacological activity of junctional transmitter. As such, various monoaminergic opioids in vitro can still be complex, however, because (NA, DA,5-HT), GABA, glutamate (NMDA/AMPA) more than one opioid receptors type is present in many pathways are intricately involved in opioid actions [1]. tissues. Opioid receptors are present in a variety of Opioid receptor activation reduces intracellular peripheral tissues, and isolated tissue preparations, cAMP formation and open K+channels (mainly through µ particularly the guinea pig ileum (GPI) and mouse vas and k receptor) or suppresses voltage gated N type Ca2+ deferens (MVD), have been routinely used to assess opioid channels (mainly µ receptor). These actions result in activity. Radioligand binding assays for each of the opioid neuronal hyperpolarization and reduced availability of receptor types have been instrumental in the identification intracellular Ca2+- decreased neurotransmitter release by of selective opioids. With the cloning of the opioid cerebral, spinal and myenteric neurone (e.g. glutamate from receptors, assays for both opioid receptors affinity and primary nociceptive afferents). efficacy can now be routinely performed by use of these cells that express only a single receptor type, greatly Structure of intracellular and extracellular mechanism simplifying the interpretation of the results of the assays [5- of opioid receptors 7].  Each transmembrane helix is labelled with a roman The presynaptic action of opioids to inhibit number. neurotransmitter release is considered to their major effect  The white empty circles represent non conserved in the nervous system. Opioid drugs act in both the central amino acid among the MOP, KOP, DOP, and NOP and peripheral nervous systems. The central nervous system receptors. opioids have effects in many areas including the spinal cord;  Violet circle with a letter represent further identity peripheral nervous system actions of opioids in both the between the MOP-R, DOP-R and KOP-R. myenteric plexus and submucous plexus in the wall of the  Green circles highlight the highly conserved fingerprint gut are responsible for the powerful constipating effects of residues. opioids.  Yellow circles depict the two conserved cystines in EL loops 1 and 2 likely forming a disulfide bridge. Transducer mechanism  IL- Intracellular loop and EL- Extracellular loop.4 All three type of opioid receptors that is mu (µ),

Table 1. Opioid Receptors and their subtypes Receptor Types and subtypes (Natural Location Function Selective agonist Selective antagonist ligand) Respiratory Morphine depression, Naloxone µ, Mu, OP3 Miosis, Naltrexone DAMGO (Tyr-D-Ala- (endormorphin-1) Brain, Cortex Euphoria, CTOP MePhe-NH-(CH2)2OH (endormorphin-2) (laminae 3 and 4) Muscular PLO17 (Tyr-Pro-MePhe-D- (β-endorphin)* rigidity, sedation, Β-FNA Pro-NH2) Physical s (affinity label) BIT (affinity label) dependence Analgesia, Naloxonazine Meptazinol µ1 (high affinity) Brain Physical Etonitazene dependence Respiratory depression, Cortex (laminae 3 and miosis, euphoria, TRIMU-5 (Tyr-D-Ala-Gly- µ2 (low affinity) 4) reduced GI NH-(CH2)2-CH-(CH3)2 motility, physical dependence Analgesia, Ethylketocyclazocine , Kappa, OP2 Brain, spinal cord, diuresis, (EKC) TENA (dynorphin) peripheral sensory dysphoria, Bremazocine nor-BNI (β-endorphin)* neuron miosis, Mr2034 65 | P a g e

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neuroprotection, Dyn (1-17) sedation, stress Trifluadom U-50,488 Spiradoline (U-62,066) 1 (high affinity) Brain Analgesia UPHIT U-69,593 PD 117302 Diuresis, Spinal cord, dysphoria,miosis, 3 NalBzOH peripheral neurons neuroprotection, sedation,stress Analgesia, DADLE (D-Ala2-D-Leu5- Brain, antidepressant enkephalin) ICI 174864  Delta,OP1 Amygdala, olfactory effect, DSLET (Tyr-D-Ser-Gly- FIT (affinity label) (enkephalins) bulbs, deep cortex, convulsant Phe-Leu-Thr) SUPERFIT (affinity (β-endorphin)* peripheral sensory effects, physical DPDPE (D-Pen2-D-Pen5- label) neurons dependence, Enkephalin) Analgesia, (NTI)  Brain antidepressant DADLE 1 BNTX effect Amygdala,olfactoryb Convulsant (NTB) ulbs,deep cortex, 2 effects, physical D-Ala2- 2 Naltrindolisothiocynate peripheral sensory dependence (NTII) neurons Nociception/ Orphan Brain, cortex, spinal Anxiety, receptor cord, amygdala, depression OP4 hypothalamus

Table 2. Classification of “Opioid Receptors” subtypes and action from animal model Sr. No. Receptor Subtypes Action of Agonist Action of Antagonist Analgesia:-Supraspinal and µ, , 1 Analgesia No effect Spinal 2 Respiratory function µ Decrease No effect 3 Gastrointestinal tract µ,  Decrease transit No effect 4 Psychotomimesis  Increase No effect 5 Feeding µ, , Increase feeding Decrease feeding 6 Sedation µ,  Increase No effect 7 Diuresis  Increase Hormone regulation:- µ Increase release 8 Decrease release Prolactin Growth hormone µ and/ or  Neurotransmitter release:- µ 9 Inhibit Acetylcholin Dopamine µ,  Isolated organ bioassay:- µ 10 Guinea pig ileum Mouse vas Decrease contraction No effect  deferens

Table 3. Nature of interaction of opioid ligand with the three major types of “Opioid receptors”, along with equivalent analgesic doses Sr. Analgesic* dose Ligand Mu (µ) Kappa () Delta () No. (mg) Agonist (weak Agonist (weak 1 Morphine Agonist (strong action) 10 action) action) Agonist (moderate 2 Nalorphine Antagonist (strong action) _ _ action) 3 Pentazocine Partial agonist, antagonist Agonist (moderate - 30-60

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(weak action) action) Partial agonist (weak Agonist (strong 4 1-3 action) action) - Antagonist (weak 5 Buprenorphine Partial agonist - 0.3-0.4 action) Antagonist Antagonist (weak 6 Naloxone Antagonist (strong action) - (moderate action) action) Antagonist (strong Antagonist (weak 7 Naltrexone Antagonist (strong action) - action) action) Agonist (strong 8 Met/luenkephalin Agonist (moderate action) - - action) Agonist (strong 9 β-endorphin Agonist (strong action) - - action) Agonist (strong Agonist (weak 10 Dynorphin A, B Agonist (weak action) - action) action)

Fig 1. Structure of opioid receptor

ACKNOWLEDGEMENT CONFLICT OF INTEREST Nil None

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