NeuroPharmacology (NB404): Dr. Charles Chavkin Professor of Pharmacology D425 HSB

NeuroPharmacology (NB404): Opiate receptors, endogenous opioid systems in brain, Analgesia, stress adaptation, drug addiction How drugs interact with their targets. How drugs interact with their targets. How pharmacology can be used to discover new medicines. How pharmacology can be used to discover new medicines. How pharmacology can be used to increase our understanding of healthy and pathological brain functioning. How pharmacology can be used to increase our understanding of healthy and pathological brain functioning.

Natural opium alkaloids Morphine - gold standard Codeine Thebaine - (non-analgesic)

CH 3 C=0 Heroin Heroin CH 3 C=0 Opiate chemical structures Naloxone CH 2 =CH Naloxone

Endogenous Opioid Agonists: enkephalin - 2 pentapeptides  -endorphin - POMC, ACTH dynorphin - endog kappa agonist NH 2 - Tyr-Gly-Gly-Phe-Leu- COOH

NSAIDS Opioids Opioids

Types of Pain Nociceptive pain - mechanical, thermal, chemical activation of nociceptors somatic pain: response to tissue injury inflammatory mediators: prostaglandins, substance P, bradykinin Neuropathic pain - damage to nerves (trigeminal neuralgia, postherpetic pain, diabetic neuropathy)

Actions of Opiates: analgesiaanxiolyticsedationeuphoria gut hypomotility (constipation) cough suppression respiratory depression pupillary constriction nausea and vomiting nausea and vomiting endocrine suppression itching (specifically morphine)

Endogenous opioid peptides (enkephalins and  -endorphin) have Morphine-like effects Analgesia Analgesia Euphoria Euphoria Antidepressant Antidepressant Reduction in anxiety Reduction in anxiety Endogenous dynorphin opioid peptides Analgesia Analgesia Dysphoria Dysphoria Depressant ? Depressant ? Increase in anxiety ? Increase in anxiety ? Endogenous opioids form important stress regulating systems in brain Stress-induced analgesia Stress-induced dysphoria Stress-induced priming of relapse?

Day 1 Day 2 Dyn KO mice generated by Hochgeschwender; see Sharifi et al., 1998 Forced swim stress-induced analgesia is blocked by prodynorphin gene disruption

Mechanisms of opiate actions: Activate mu (  ) delta (  ), or kappa (  ) opioid receptors principal therapeutic opiates are selective for mu receptors principal therapeutic opiates are selective for mu receptors Opioid receptors are members of the 7TM, G protein- coupled receptor superfamily (>1,000 members) coupled receptor superfamily (>1,000 members) Activation of opioid receptors inhibits neuronal activity increases potassium conductance decreases calcium conductance inhibits neurotransmitter release

GDPGTP PO 4 GDP Activated arrestin G-Receptor Kinase K+K+ how do opiates act at a molecular level? opioid dose response tolerance

Opiate Tolerance receptor desensitization compensatory adaptations in neuronal circuit learning mechanisms Physical Dependence compensatory adaptations in neuronal circuit compensatory adaptations in neuronal circuit Drug Withdrawal removal of opiate unmasks compensatory adaptations Drug Addiction (extremely rare during treatment of pain)

 -arrestin produces GPCR tolerance in a series of resolvable steps GPCR-PO4 activates  -arrestin GPCR-PO4 activates  -arrestin Newly exposed  -arr domain Newly exposed  -arr domain binds GPCR GPCR-  -arr prevents G- GPCR-  -arr prevents G- protein association GPCR-  -arr complex is GPCR-  -arr complex is internalized by a dynamin and clathrin dependent mechanism G Protein receptor kinase  -arrestin

 OR RR Noradrenergic neuron in the locus ceruleus Acutely, morphine inhibits LC firing - sedation Opiates inhibit K+K+K+K+ Neuron hyperpolarized and NE release inhibited

 OR RR Noradrenergic neuron in the locus ceruleus Chronically, this causes a compensatory increase in LC activation decreased auto-inhibition, increased excitatory drive Excitatory drive RR RR Receptor desensitization Tolerance Normal Excitability restored

Opioid withdrawal - abstinence syndrome Severity depends on dose used and rate of elimination. RhinorrheaLacrimationChills Goose flesh - ‘cold turkey’ Muscle aches DiarrheaYawningAnxietyHostilityHyperalgesia Precipitated withdrawal by a partial agonist or antagonist administration

 OR RR Noradrenergic neuron in the locus ceruleus Excitatory drive RR RR Opiate gone Withdrawal Hyper-Excitability state Clonidine, an  2-adrenergic receptor agonist, is effective at reducing the sympathetic nervous system hyperactivity associated with acute opiate withdrawal.

What is drug addiction? Correct use of prescribed medications for pain, anxiety and hypertension produce tolerance and physical dependence. Addiction is: compulsive drug use, obsessive thoughts about drug, use despite objective evidence of harm, loss of control of drug use, high risk of relapse once abstinent. Commonly Abused Prescription Opiates Buprenorphine (Buprenex, Subutex, Suboxone) Codeine Fentanyl (Actiq, Sublimaze, Duragesic) Hydrocodone (Vicodin, Vicoprofen) Hydromorphone (Dilaudid) Meperidine (Demerol) Methadone (Methadose, Dolophine) Morphine (MS Contin, Avinza, Oramorph SR) Oxycodone (OxyContin, Percocet, Percodan) Propoxyphene (Darvon)

“Molecular Basis of Addiction” Voluntary intake Voluntary intake tolerance sensitization physical dependence Involuntary - compulsive intake Involuntary - compulsive intake cravings, obsession, self-destructive behavior Addiction readily reversible - high relapse risk

Progression to Addiction challenges at the molecular front challenges at the molecular front: identify molecular and cellular changes in the addicted brain genes controlling risk of addiction molecular events controlling relapse risk

Conditioned place preference measures the rewarding properties of drugs nor-BNI treated FST mice Vehicle-treated FST mice Untreated mice, no stress Difference in time spent on drug-paired side (sec) * * * Day 5 resultsBaseline Day: Free Run, 30 minForced swim stress exposure Cocaine, box 2, 30 minVehicle, box 1, 30 min assess drug craving assess drug craving

Stress-induced priming of relapse? Drug consumption time escalation crash relapse stress HeroinCocaineEthanolNicotine

Working Model - (wild speculation) Stress induces release of endogenous opioids in key brain regions (nAc and VTA). This results in ‘priming’ of the circuit - manifests as craving Activation of the endogenous kappa opioid system during the stress response elicits dysphoria, anxiety depression. Drug self-administration self medicates the depression. Kappa antagonists may be effective in treating this form of depression.

Opiates are important therapeutic tools Endogenous opioids have important role in mediating the adaptive response to stress Opiates can induce addiction - a compulsive use of drug despite adverse consequence SUMMARY: