Disclosures Non-neuronal cells amplify pain and drug reward ~ - PowerPoint PPT Presentation

“Listening” and “Talking” to Neurons: Disclosures Non-neuronal cells amplify pain and drug reward ~ Pathways from basic science to human and veterinary clinical trials ~ n Xalud Therapeu6cs: 
 Research funding from: 
 n > NIH (NCCIH, NIDCR, NIDA, NINDS, NIMH) 
 > Co-Founder 
 Linda R. Watkins > Department of Defense 
 > Co-Chair Sci Advisory Board > ALS Alliance; Prize4Life (ALS) 
 Early stage startup; Psychology & Neuroscience, University of Colorado-Boulder > NaAonal MulAple Sclerosis Society 
 co-Founder & co-Chair Scientific Advisory Board, Xalud Therapeutics en6rely Preclinical (no > McManus Charitable Trust 
 marketed products), > Paralyzed Veterans of America 
 developing non-opioid > Craig Spinal Cord Injury Hosp. 
 Yip! Yip! immunomodulatory pain > Craig Neilson FoundaAon 
 Hooray! therapeu6cs > Wings for Life 
 Human Clinical Trials > American Kennel Club 
 for Osteoarthritis pain > MayDay Fdn; Cielo Fdn 
 now underway in U.S. > Chancellor’s Fund, CU 
 (California) & Australia > Ohio Vet. Med. Assoc. (Adelaide) !!! 1 2 “Listening” and “Talking” to Neurons: Global Concepts Non-neuronal cells amplify pain and drug reward ~ Pathways from basic science to human and veterinary clinical trials ~ Views of pathological pain are changing n RecogniAon of Non-Neuronal players in pain: glial cells n Linda R. Watkins ( microglia & astrocytes) in spinal & brain pain pathways; Psychology & Neuroscience, University of Colorado-Boulder peripheral immune cells in involved Assues co-Founder & co-Chair Scientific Advisory Board, Xalud Therapeutics RecogniAon of Non-Neuronal players in opioid ac2ons: n Glia disrupt the clinical efficacy of opioids, including morphine, oxycodone, remifentanyl, methadone, etc. Clinical implicaAons of glial dysregulaAon of pain & opioid n acAons ... glia/immune targe2ng therapeu2cs are approaching clinical trials! 3 4

Global Concepts Global Concepts Views of pathological pain are changing Views of pathological pain are changing n n RecogniAon of Non-Neuronal players in pain: glial cells RecogniAon of Non-Neuronal players in pain: glial cells n n ( microglia & astrocytes) in spinal & brain pain pathways; ( microglia & astrocytes) in spinal & brain pain pathways; peripheral immune cells in involved Assues peripheral immune cells in involved Assues RecogniAon of Non-Neuronal players in opioid ac2ons: RecogniAon of Non-Neuronal players in opioid ac2ons: n n Glia disrupt the clinical efficacy of opioids, including Glia disrupt the clinical efficacy of opioids, including morphine, oxycodone, remifentanyl, codeine, etc. morphine, oxycodone, remifentanyl, methadone, etc. Clinical implicaAons of glial dysregulaAon of pain & opioid Clinical implicaAons of glial dysregulaAon of pain & opioid n n acAons ... glia/immune targe2ng therapeu2cs are acAons ... glia/immune targe2ng therapeu2cs are approaching clinical trials! approaching clinical trials! 5 6 Global Concepts Views of pathological pain are changing n RecogniAon of Non-Neuronal players in pain: glial cells n ( microglia & astrocytes) in spinal & brain pain pathways; peripheral immune cells in involved Assues RecogniAon of Non-Neuronal players in opioid ac2ons: n Glia disrupt the clinical efficacy of opioids, including morphine, oxycodone, remifentanyl, methadone, etc. Clinical implicaAons of glial dysregulaAon of pain & opioid n acAons ... glia/immune targe2ng therapeu2cs are approaching clinical trials! 7 8

What Have the Past 25+ Years Revealed? ~ Beyond Pain ~ (Watkins et al. , Brain Behav Immunity 2007; For Opioids: The Data Support That Blocking Grace et al. , Nature Reviews Immunology 2014) Glial/Immune Activation Will: Spinal & trigminal glia (microglia, astrocytes) are ac2vated in every clinically-relevant model of enhanced pain : v Improve opioid analgesia • SomaAc (sciaAc etc.) & trigeminal injury • TMJD, occlusal interference v Suppress opioid tolerance • Chronic tooth pulp inflammaAon • “Migraine” facial allodynia v Suppress opioid dependence • Bone cancer; chemotherapy • MulAple sclerosis v Suppress opioid reward linked to 
 • Spinal cord injury • Radiculopathy/herniated discs, and so on… drug craving/drug abuse Suppressing spinal & trigeminal glial acAvaAon v Suppress both opioid-induced 
 &/or glial proinflammatory cytokines: f • suppresses pain in every clinically-relevant respiratory depression & constipation model, returning pain to normal 9 10 Microglia Actively Survey the CNS & Microglia Actively Survey the CNS & Rapidly Respond to Challenge Rapidly Respond to Challenge Videos from: Davalos et al., Nature Neuroscience supplements, 8 (2005) 752-758; Videos from: Davalos et al., Nature Neuroscience supplements, 8 (2005) 752-758 & Nimmerjahn et al., Science supplements, 308 (2005) 1314-1318 11 12

Glia Release Neuroexcitatory, Glial ProinRlammatory Cytokines: 
 Pain Enhancing Substances Major Players in Neuroexcitation in Pain 
 (Watkins et al. , Brain Behav Immunity 2007) ... as well as Opposing opioid analgesia! AcBvated glia release: Proinflammatory Cytokines: Arachidonic acid & Proinflammatory prostaglandins cytokines, chemokines Tumor Necrosis Factor Interleukin-1 Enkephalinases Excitatory amino acids Interleukin-6 ReacAve oxygen Nerve growth factors species; NO Neuroexcita2on! • Amplify pain signaling from the body to the spinal cord • Amplify pain transmission from the spinal cord to the brain: By Enhancing pain, • upregulate AMPA & NMDA receptor number/funcBon Movie of glial cell from Mike Dailey’s website, U Iowa (Adrienne Benediktsson & Ryan Jeffrey) Opposes opioid analgesia • downregulate GABA & outward K+ currents • downregulate glial glutamate transporters & GRK2 13 14 What Activates Glia? What Activates Glia? Proinflammatory cytokines Proinflammatory cytokines Heat shock proteins Heat shock proteins CGRP CGRP Substance P Substance P Fractalkine Fractalkine ATP ATP Prostaglandins Prostaglandins Glutamate Glutamate Nitric oxide Nitric oxide Alcohol, Endogenous danger signals Alcohol, Cocaine Methamphetamine, Endogenous danger signals Opioids Opioids Cocaine Watkins & Maier , Nature Rev Drug Disc 2003 Watkins & Maier , Nature Rev Drug Disc 2003 Hutchinson et al. , Pharmacol Reviews 2011 Hutchinson et al. , Pharmacol Reviews 2011 15 16

Glial Activation by Endogenous Danger Signals What Activates Glia? Endogenous danger signal ac6va6on of glia (microglia, astrocytes) implicated in pain in mul6ple rodent models, such as: Proinflammatory cytokines Heat shock proteins • Peripheral nerve injury • Medica6on overuse headache, migraine CGRP Substance P • Streptozotocin diabe6c neuropathy Fractalkine • Spinal cord injury ATP • Bone cancer Prostaglandins • Arthri6s Glutamate • Pancrea66s Nitric oxide • Mul6ple sclerosis Alcohol, When bad things happen ... endogenous Methamphetamine, Endogenous danger signals Opioids danger signals are created ... glia are Cocaine Watkins & Maier , Nature Rev Drug Disc 2003 activated... pain is amplified by glial pain- Hutchinson et al. , Pharmacol Reviews 2011 enhancing proinflammatory cytokines Bachtell et al., CNS Neurol Disord Drug Targets 2015 ~ Hence perfect target for therapeutics that elevate ANTI-inflammatory cytokines like Interleukin-10 17 18 Spinal Glial Activation Opposes the What Activates Glia? Ability of Opioids to Suppress Pain Morphine & Methadone as examples Proinflammatory cytokines Heat shock proteins CGRP Substance P Intrathecal (i.t.; into cerebrospinal <luid over spinal cord) Fractalkine Morphine R-Methadone [-] Percent of Maximal Possible Effect 100 100 ATP i.t. IL-1ra i.t. IL-1ra Prostaglandins 75 75 Glutamate Nitric oxide 50 50 Alcohol, 25 Morphine 25 Methadone Endogenous danger signals Methamphetamine, Opioids Cocaine 0 0 Watkins & Maier , Nature Rev Drug Disc 2003 Saline Control Saline Control Hutchinson et al. , Pharmacol Reviews 2011 BL 5 25 45 65 85 105 125 145 165 185 BL 5 25 45 65 85 105 125 145 165 185 Timecourse (Minutes) Timecourse (Minutes) Bachtell et al., CNS Neurol Disord Drug Targets 2015 Hutchinson et al., Brain Behavior & Immunity, ‘08 19 20

Blocking Spinal Interleukin-1 Blocking Spinal Interleukin-1 Unmasks Morphine Analgesia Unmasks Morphine Analgesia Blocking glial activation improves the efficacy of opioids for pain control Morphine Morphine Analgesia Analgesia Behavioral output =Morphine + IL-1 Pain Pain IL-1 receptor Interleukin-1 : Neuroexcitation which antagonist Opposes analgesia (IL-1ra; Anakinra) Interleukin-1 Hutchinson et al. , Brain Behav Immunity 2008 Hutchinson et al. , Brain Behav Immunity 2008 21 22 Mirror Image Molecules Opioid effects are different for ....but, for neurons , not the same! neurons & glia Opioids exist as mirror-image stereo-isomers (-)-Morphine (+)-Morphine • Binds to µ-opioid receptors • NO binding to µ-opioid receptors • Powerful analgesic • NO analgesia thanks to Dr. Kenner Rice 23 24