Emerging Delta and Kappa Agonist Therapies

Emerging Delta and Kappa Agonist Therapies John Peppin, DO, FACP

Disclosure  Consultant/Independent Contractor: AIT Laboratories, Ameritox Laboratories, Grünenthal Pharmaceuticals, INSYS Therapeutics, Salix Pharmaceuticals  Honoraria: AIT Laboratories, Ameritox Laboratories, Depomed Pharmaceuticals, Grünenthal Pharmaceuticals, INSYS Therapeutics, Salix Pharmaceuticals  Speakers Bureau: Salix Pharmaceuticals

Learning Objectives  Recall the initial research regarding the use of opioids for pain management  Describe the physiology of the delta and kappa opioids  Review current and emerging delta and kappa opioid agents

Delta and Other Opioids  Overview – Introduction – Opioid Physiology – Delta Opioid Physiology – Kappa Opioid Physiology – Clinical Status – Conclusion

Delta and Other Opioids  Introduction – Opioids used for millennia.

• Hippocrates and Thomas Sydenham – Extoled virtues of the “poppy”.

– “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”

– Opioids have helped millions • But a “down side”

Delta and Other Opioids  Introduction – Opioid Down Side • Side effects: – Constipation, urinary retention, somnolence, pruritis, potential osteoporosis endocrinopathies etc…

• Unique: – Addiction, abuse, diversion and overdose deaths.

– 170,000 “doctor shoppers” for oxycodone and hydrocodone, per the USA – GAO – 2008 36,450 OD deaths, 14,800 opioid related deaths (CDC, 2011)

Delta and Other Opioids  Introduction – Current Problems • Efficacy of > 30% unusual regardless of treatment • Expense, long term use etc..

– Need to new agents • Improve analgesia • To reduce side effects • To reduce Societal impact and expense

GENERAL PHYSIOLOGY

Delta and Other Opioids  Physiology – Signals C and A delta fibers • Skin, bone, muscle, viscera • Cell bodies in dorsal root ganglia • Release neurotransmitters to second order neurons • Tertiary neurons send signals to cortex – Pain and behavioral response

Delta and Other Opioids  Physiology – Opioid receptors identified 25 years ago (Pert, 1973) – Cloned μ, κ, and δ receptors • Highly homologous, 65 % (Reisine, 1995)

– Affinity of morphine for μ 50x higher than δ (Emmerson, 1994) – Interact with heterotrimeric G proteins (Gilman, 1987; Childers, 1991).

Delta and Other Opioids  Physiology – G Protein coupled receptors (GPCR) • 7 Transmembrane domaines • Tranduction – By cAMP and phosphatidylinositol signal pathway

• Involved in wide variety of physiologic processes • Activation – Ligand binding to external portion – Conformational change – Action

Delta and Other Opioids  Physiology – G-Protein Coupled Receptors (GPCR) • Multiple families – opioid receptors Type A or rhodopsin-like GPCRs – 2,000 GPCRs within the rhodopsin family (Stevens 2009)

• Target for > 60% pharmaceuticals • “While there appears to be no limit to the effects of opioids, both endogenous and exogenous, on any system in the brain and body, underlying all opioid effects is the fundamental event of an opioid agonist binding and activating an opioid receptor.” (Stevens, 2009)

Delta and Other Opioids  Physiology – Binding to respective GPCR • Inhibit calcium influx  Increase potassium eflux • Hyperpolarization, reduced pain signal.

– “Opioidergic pain control” • Affects multiple neuraxis levels (Vanderah, 2010) • Kappa and Delta – Periphery, dorsal root ganglia, spinal cord, supraspinal areas (PAG, RVM)

• Delta agonists can activate pain inhibitory pathways.

• OFF cells in dorsal horn activated by delta agonist

Delta and Other Opioids  Physiology – Opioid Receptors • Now at least 20 alternative splice variants of mMOR • At least 6 variants of MOR – Many show different ligand binding or signaling pathways

• Only a few alternative spice variants for KOR • Even less for DOR and ORL (Stevens, 2009)

Delta and Other Opioids  Physiology – Differences between sexes • Women respond better to agonist/antagonist, e.g., butorphanol (Sibillie, 2011) • Women respond less to morphine (Cook, 2000) • Woman responded to Kappa agonists greater than men (Gear, 1996) • No sex significant differences in delta opioid agonist (Kepler, 1991 & Bartok, 1997)

Delta and Other Opioids  Physiology – Opioid Actions (Bodnar, 2007) • • • • • • • • • •

Stress and Social status Depression and Anxiety Learning and Memory Sexual activity Pregnancy Endocrine effects Renal and hepatic functions GI function Immune function Thermoregulation

DELTA OPIOID PHYSIOLOGY

Delta and Other Opioids  Delta Opioid Physiology – Encephalins/Deltorphin-natural peptide agonists – Delta receptor homeostatic state • Intracellular within neurons • Inflammation causes receptor migration – Membrane surface, Dorsal spinal cord (Vanderah, 2010)

• Inflammation required to induce activated δ receptors

Delta and Other Opioids  Delta Opioid Physiology – Humans tracer uptake for DOR • Highest in basal ganglia and neocortical regions • Lowest in thalamus and cerebellum

 Areas of higher DOR concentration  Areas of less DOR concentration

Pradhan, 2011

Delta and Other Opioids  Delta Opioid Physiology – Delta receptor homeostatic state • Extended administration of morphine – Induces movement of delta opioid receptors to membrane in superficial dorsal horn layers (Morinville, 2004) » Receptor function also effected. » Mu opioid receptors may regulate delta opioid receptor surface expression » Heterodimerization » Mu may be required for delta opioid receptor trafficking and action. » May cause seizure at higher doses

Delta and Other Opioids  Delta Opioid Physiology – Behavioral Effects • Antidepressant and anxiolytic effects (Stevenson, 2003) • Robust in animals (Broom, 2002).

• Central Delta Opioid pathways involved in emotional behavior control • TCA – Increased naloxone brain binding sites (Baraldi, 1983)

• Upregulation of encephalin with ECT (Hong, 1979) • Inhibition of encephalinases produces antidepression (Baamonde, 1992)

Delta and Other Opioids  Delta Opioid Physiology – Certain Delta Opioid Agonists • May prevent cardiac and cerebral ischemia – http://ksef.kstc.com/Dynamic/Awards/Commfund_Abstract.cfm?ContactID=COMMF UND-1108-RFP-007. Accessed February 15, 2010.

• Rubiscolin – Which has been shown in one study to improve & enhance memory. (Yang, 2003),

Delta and Other Opioids  Delta Opioid Physiology – Reduced abuse potential in rodent and primate studies (Vanderah, 2010) – Minimal effects of respiratory function and GI function, vide infra – Potential benefits • Improved neuropathic pain treatment • Reduced respiratory depression • Reduced constipation • Reduced physical dependence

KAPPA OPIOIDS

Delta and Other Opioids  Kappa Opioid Physiology – Once Kappa inside BB barrier • Dysphoria becomes limiting SE (Vanderah, 2009) • Expression may be dependent on estrous cycle • Proof of concept studies – Kappa agonist must be peripherally restricted » Avoids CNS SE

• May have role in reduced addiction

Delta and Other Opioids  Kappa Opioid Physiology – Dynorphin-endogenous ligand – Found in hypothalamus, PAG and claustrum • Substantia gelatinosa • Nociceptors

– Regulate serotonin through 38 mitogen-activated protein kinase (p38 MAPK) (Bruchas, 2011) • p38MAPK required for behavioral changes, not for analgesia • p38MAPK prevents delta agonists from being rewarding

Delta and Other Opioids  Kappa Opioid Physiology – DOR agonist Investigated in 1980s • Investigation given up due to dysphoria, hallucinations (Pfeiffer, 1986)

– “To achieve analgesia without unleashing unwanted side effects, the trick is to find small molecules that selectively stabilize the desired conformations.” (Whalen, 2011).

• K1 receptor cloned, not other subtypes • No specific ligands for subtypes • K1 receptor and K1 agonist

Delta and Other Opioids  Kappa Opioid Physiology – Role in addiction – Kappa receptors found in somatic and viscera • Especially in inflammatory states (Riviere, 2000) – Higher concentration in immune cells than MOR

• Effective in wide variety of visceral pain models – – – – –

Irrespective of species Peritoneal irritation models Peripheral receptors, not central effect Suggestive in post op ileus models (Friese, 1997) Irritable Bowel Syndrome (Dapoigny, 1995)

Delta and Other Opioids  Kappa Opioid Physiology – Differences between sexes • Woman responded to Kappa agonists greater than men (Gear, 1996)

Delta and Other Opioids  Kappa Opioid Physiology – Mediation of stress responses: Dynorphin (Land, 2008) – Also CRF – Nalbuphine, pentazocin, butorphanol – Mixed KOR and MOR agonists • Great interest • May show reduced hyperalgesia • Reduced tolerance • Less physical dependency

CLINICAL STATUS

Delta and Other Opioids  Clinical Status – Work on Delta and Kappa opioids was stopped due to dysphoria, seizures etc..

– Work on Delta and Kappa opioids has been resumed • Due to our previous discussion

DOR Agents

DOR Agents

KOR Agents

CONCLUSION

Delta and Other Opioids  Conclusion: MOR/DOR agonists – MOR/DOR form heterodiemers • Not demonstrated in KOR • Close interaction – DOR needs MOR agonism – Both increased with inflammation

Delta and Other Opioids  Conclusion: MOR/DOR agonists – MOR/DOR agonist • DOR agonist suppress tolerance, physical dependnce and side effects of MOR stimulation – DOR knock-out mice document role in development of tolerance

• May have less opioid related side effects – Naltrindole reversed alfentanil induced respiratory depression (Freye, 1992) – Delta Agonist enhanced colonic propolsion (Foxx-Orenstein, 1998)

• May treat depression/anxiety as well as analgesia

Delta and Other Opioids  Conclusion – KOR • Must be peripherally compartmentalized • Potential in visceral pain – Post operative Ileus, pancreatitis, labor pain, IBS, etc..

– But studies used peripheral localized agonists

Delta and Other Opioids  Conclusion – Need for new analgesics • Less side effects, better efficacy, multiple actions

– DOR and KOR agonists may provide this alternative

Delta and Other Opioids  Overview – Introduction – Opioid Physiology – Delta Opioid Physiology – Kappa Opioid Physiology – Clinical Status – Conclusion