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PRESENTED BY - VARSHA SONAWANE M.PHARM (SEM-) DEPARTMENT OF PHARMACOLOGYR. C . PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH , SHIRPUR . OPIOID RECEPTOR

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CONTENTSHistoryIntroductionStructure,Classification, Receptor stimulators & NomenclatureMechanism of actionPain pathwayDistributionSide effectsRecent advances

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HISTORY Pain Physician ;2008 The opium poppy was cultivated as early as 3400 BC in Mesopotamia. Solomon Snyder and colleagues, first identified opioid receptors in the brain in 1975.Acheson coin the term OPIOID. In 1960s, T sou and Jang performed a pioneering work in understanding the mechanism.

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INTRODUCTION Tripathi K.D;2003Algesia : means pain (unpleasant sensation),evoked by external or internal stimulus.Analgesic : is a drug relives pain by acting on CNS or on peripheral pain mechanism, without altering consciousness.

Analgesic

Opioid/NarcoticNon- opioid /non narcotic4

OPIATEOpiates are group of drug that are use to treating pain OPIATE ADDICTION Opiates produce a sense of wellbeing. A high dose of opiate can cause death from cardiac or respiratory arrest.OPIATE WITHDRAWAL SYNDROME INCLUDES: Low energy, irritability , anxiety , insomnia , agitation , Runny nose, teary eyes, Hot and cold sweat , goose bumps , Yawning, Muscle ache and pains Abdominal cramping , nausea ,vomiting , diarrhoea.

Dr Mahesh Trivedi;20075

Ashley Rogers & Eric Walker

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PAIN PATHWAY RECEPTOR (nociceptors)7 A-delta fibres(myelinated)(fast 15-20 m/sec)C-fibres (unmyelinated)(slow 1-2m/sec)Dorsal columnsVentrolateral columnsThalamic nuclei Thalamohypothalamic projection

STRUCTURE OF OPIOID RECEPTOR

N-terminalC- terminalTM7TM1TM2TM3TM4TM5TM6EL1EL2EL3IL1IL2IL38

HOW DO OPIOID ACT9 Interact with specific cell surface receptor in CNS and PNS Other tissue ( GIT Immune cells other tissues)

2 nd messenger systemG proteinsG proteinsG protein

CLASSIFICATION OF OPIATES

OpiumOpiumMorphine Codeine ThebainOpiate derivativeHeroinHydromorphoneOxymorphineOxycodoneEtrophineSynthetic opiateMethadone MepiridinePropoxypheneLAAM10

CLASSIFICATION OF OPIOID RECEPTOR 11Types1231

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Novel typeSigma receptor

NOMENCLATURE Dr. Mahesh Trivedi,2007Nomenclature approved by International Union of Pharmacology for identification of the opioid receptors:

MOP (mu opioid peptide receptor)

KOP (kappa opioid peptide receptor)

DOP (delta opioid peptide receptor)

NOP (nociceptin orphanin FQ peptide receptor)

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RECEPTORENDOGENOUS LIGAND EFFECT ON RECEPTOR STIMULATIONMu()EndorrphinSupraspinal analgesia (1)Dependance (2)Respiratory depression (2)Constipation (2) , miosis (2) Kappa()DynorphinSpinal analgesia Sedation Miosis Delta()EnkephalinsRespiratory depressionSigma()UnknownDysphoriaHallucinations

OPIOID RECEPTORS, THEIR ENDOGENOUS LIGANDS AND EFFECT PRODUCED ON RECEPTOR STIMULATION13

TRANSDUCTION MECHANISM Transduction mechanism through G couple receptor 14

CELLULAR RESPONSE BY OPIOID RECEPTOR Dr Mahesh Trivedi

Opioid receptors are couple with inhibitory G protein and there activation has number of action including :Closing of voltage sensitive calcium channels.Stimulation of potassium efflux leading to hyperpolarisation and reduce cyclic adenosine monophosphate production.Overall effect in the reduction of neuronal cell excitability that result in reduced transmission of nociceptive impulses.

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DISTRIBUTION OF OPIOID RECEPTOR16

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MAJOR SIDE EFFECTS OF OPIOID AGONISTS CVS: Decrease systemic BPCNS: Miosis Stiff chest syndrome

RESPIRATORY SYSTEM: depression of respiratory system by receptor.

Robert K. Stoelting;2oo718

BILIARY & GI TRACT: Spasm of biliary smooth muscles (constipation Effect mediated by & receptor).

Nausea & vomiting Tolarance & physical dependance

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MARKETED PREPARATIONS OF OPIOIDS

MORCONTIN (Morphine) RILIMORPH (Morphine) DUROGESIC (Fentanyl) PHYSEPTONE (Methadone) PARVON & PARVODEX (Dextropropoxyphene) DOMADOL (Tramadol)20

ADVANCES IN RESEARCH ON OPIOID RECEPTOR FUNCTIONOpioid peptide receptors in the CNS represent the peptidergic transmission system and are widely involved in various pleiotropic functions They are essential for various physiological functions including:

Yuan Feng,et al;201221

Ionic homeostasis Cell proliferation NeuroprotectonHibernationPain modulation Drug abuse / addiction

Emotional response Epileptic seizuresImmune functionObesityRespiratory control Cardiovascular regulation

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IONIC HOMEOSTASIS overall effect of Ca 2+ on homeostasis is inhibitory but , some studies shows that opioid receptor activates Ca2+ channel.

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CELL PROLIFERATION Opioid receptor affect cell proliferation. delta opioid receptor play important role in the neurogenesis & neuroprotection. Some studies have shown that the OGF-OGFr system is biological regulator of cell proliferation in some cancers including ovarian cancer, hepatocellular cancer, and so on.

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NUROPROTECTION The DOR neuroprotection involves the stabilization of ionic homeostasis. Administration of MOR and KOR agonists (DAMGO and 488H respectively) did not induce appreciable neuroprotection.

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HIBERNATION Mammalian hibernation is a energy-conserving state. (MOR,DOR and KOR) levels in the brain of hibernating animals is decrease on Administration of opioid antagonists effectively reversed hibernation and prevent the animals from their stupor.

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DRUG ADDICTION / ABUSE Drug abuse induces adaptive changes in opioid receptors that occurs due to acute and chronic opioid administration. Development of clinically effective agents that minimize the risks for abuse.

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FEEDING Syndyphalin-33 (SD33) - a -opioid receptor ligand, increases food intake in sheep through i.v route, and its effects are mediated via opioid receptor.OBESITY Stimulation of - opioid receptors preferentially increases the intake of a high fat diet.

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EMOTIONAL RESPONSE Delta opioid receptor act as inhibitor of stress & anxiety. KOR mediates antidepressant-like effects by BDNF gene regulation. IMMUNE FUNCTION Morphine differentially modulates LPS induced expression of IL-6 and TNF-, and it found the naltrexone was capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF- production.

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RESPIRATORY FUNCTION There are high densities of opioid receptors in the brain areas related to respiration. Depress the activity of respiratory related neurons. CARDIOVASCULAR REGULATION A MOR agonist, was found to stimulate excretion of urine sodium & potassium that suppresses the stress-induced elevation in blood pressures and heart rate.

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USE OF OPIOID FOR THE CANCER PAIN 31

Total no of patient 186 having 2 groups 74 % morphine responder26% morphine non responder

Great results on cancer pain with less side effectsAlso gives best results on cancer pain Morphine treatment for at least 4 weeks Oxycodone treatment for at least 4 weeks

OPIOID SWITCHING STUDIES

Joanne Droney;2009

In vivo neuronal co-expression of mu and delta opioid receptors Recently addressed in vivo mu-delta co-localization. To identify neurons in which receptor interactions could take place , they designed a unique double mutant knock-in mouse line that expresses functional red fluorescent mu receptors and green-fluorescent delta receptors.

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LIGAND DESIGN FOR THE KAPPA OPIOID RECEPTOR VTV Molecular Modelling ;2013Salvia divinorum originates from Mexico and contains Salvinorin A.Most potent naturally occurring hallucinogen.Has a high affinity for the - opioid like receptor.Decrease of - opioid receptor (KOPr) activity is effective in addiction therapy and depression treatment.Aim is to design a ligand that is comparable to Salvinorin A or other commercially known agonists, but with a better fit into the active site of the - opioid receptor.

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REFERENCES Andrea . M et al , opioid pharmacology , pain physician; 2008.Dr. Mahesh Trivedi , shafee shaikh et al , pharmacology of opioid part 1 anasthesia Tutorial of the week 64; 2007. Erich Erbs & Lauren faget , Receptors & clinical investigation 2014 ; 1 : e210Joanne droney et al , recent advances in use of opioid for cancer pain , journal of pain research ; 2009.Shana .L , Bowman et al , cell autonomous regulation of Mu opioid receptor recycling by substance P ;2015.Tripathi K. D , Essential of medical pharmacology , 6th edition , jaypee brothers medical publishers (p) LTD ; 2006 : 453.Yung feng ,Lawrence H . et al current research on opioid receptor function ,curr drug target ; 2012 ;13(2) : 230-246.

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