ognizant Communication Corporation

REVIEWS IN ANALGESIA
(formerly ANALGESIA)

ABSTRACTS
VOLUME 7, NUMBER 1

Reviews in Analgesia, Vol. 7, pp. 1-23
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Purinergic Modulation of Pain

Michael F. Jarvis

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6125

The metabolic degradation of ATP to adenosine (ADO) provides an array of purinergic signaling molecules that can interact with a large population of cell surface receptors that include the ATP-sensitive ionotropic P2X and metabotropic P2Y receptor superfamilies, as well as the P1 ADO-sensitive G-protein-coupled receptors. In the context of neurotransmission, ADO functions as an endogenous inhibitory neuromodulator that limits tissue trauma and inflammation, and alleviates pain. In contrast, ATP, acting at sensory neuron-specific homomeric and heteromeric P2X3-containing channels, contributes to neural excitability, is pronociceptive, and likely participates in the sensitization of the central nervous system during chronic pain. Advances in the pharmacology of purinergic neurotransmission has led to the development of new strategies to enhance the endogenous actions of ADO and to limit the neuroexcitatory effects of ATP. Two of these strategies, the development of selective adenosine kinase inhibitors and P2X3 receptor-selective antagonists, are highlighted in this review of the recent developments in the pharmacology of purinergic modulation of nociceptive signaling.

Key words: Purinergic modulation; Nociceptive Signaling; ATP; Adenosine; Chronic pain

Address correspondence to Michael F. Jarvis, Ph.D., Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, D-4PM AP-9A/3, 100 Abbott Park Rd., Abbott Park, IL 60064-6125. Tel: (847) 937-3919; Fax: (847) 937-9195; E-mail: michael.jarvis@abbott.com




Reviews in Analgesia, Vol. 7, pp. 25-39
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Analgesic Effects of Cannabinoids: Sites and Mechanisms of Action

Victoria Chapman and David P. Finn

Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, E Floor Medical School, Queen's Medical Centre, Nottingham NG72UH, UK

Cannabinoid agonists, which act at the cannabinoid1 (CB1) receptor and cannabinoid2 (CB2) receptor, have a number of physiological effects and considerable therapeutic potential, in particular as analgesics. Understanding the sites and mechanisms of action of cannabinoids that result in these analgesic effects is important for the effective therapeutic use of cannabinoids. This review discusses the results of recent preclinical studies of cannabinoid agonists in animal models of pain. Endocannabinoids, constituents of herbal cannabis and synthetic cannabinoid agonists, have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. Studies using local administration of cannabinoid agonists have shown that peripheral, spinal, and supraspinal cannabinoid receptors mediate cannabinoid-induced antinociception. The majority of evidence has pointed to a contribution of the CB1 receptor in mediating the analgesic effects of cannabinoids. The importance of peripheral CB2 receptors, however, in mediating cannabinoid-induced antinociception, in particular in models of inflammatory pain, has recently been demonstrated.

Key words: Cannabinoids; Cannabinoid agonists; Endocannabinoids; Receptor-mediated analgesia; Antinociceptive effects; Therapeutic potential

Address correspondence to Victoria Chapman, Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, E Floor Medical School, Queen's Medical Centre, Nottingham NG72UH, UK. Tel: 0044 (0) 1159709459; Fax: 0044 (0) 1159709259; E-mail: Victoria.chapman@nottingham.ac.uk




Reviews in Analgesia, Vol. 7, pp. 41-60
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

New Breakthroughs in the Regulation of G-Protein Signaling: Implications in Mu and Delta Opioid Receptor-Mediated Analgesia

Javier Garzón and Pilar Sánchez-Blázquez

Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, E-28002 Madrid, España (Spain)

The present understanding of opioid pharmacology has been influenced by discoveries relating to the mechanisms that operate on G-protein-coupled receptor (GPCR) signaling. Over the last decade, new concepts have been gradually substantiated, such as receptor preference for the regulation of certain classes of G-proteins in cells, agonists' selection of G-protein classes for internalizing their effects, and the regulation of the functional state of Ga subunits and Gbg dimers shuttling between activated receptors and effectors during agonist signal propagation. Current research is providing new information on how transduction regulated by mu and delta receptors influences the analgesic efficacy of their agonists. This includes aspects such as the Gbg binding phosducin-like proteins (PhLP) and the Ga-GTP binding regulators of G-protein signaling (RGS) proteins. These regulatory proteins emerge as being involved in controlling opioid receptor phosphorylation uncoupling, modulating the potency and duration of agonist analgesic effects, and the development of tachyphylaxis and acute tolerance to opioid analgesia.

Key words: G-Protein signaling; Opioid analgesia; Signaling regulation; RGS proteins

Address correspondence to Javier Garzón, Neurofarmacología, Instituto Cajal, CSIC. Avd Doctor Arce, 37. E-28002 Madrid, Spain. Tel: 34 91 585 4733; Fax: 34 91 585 4754; E-mail: jgarzon@cajal.csic.es




Reviews in Analgesia, Vol. 7, pp. 61-68
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The Role of Electroconvulsive Therapy in Chronic Pain

Keith G. Rasmussen

Mayo Clinic Department of Psychiatry and Psychology, 200 First St. SW, Rochester, MN 55905

Electroconvulsive therapy (ECT) has been used for over 60 years to treat psychiatric disorders, most notably affective illness such as major depression. A body of literature also describes the use of ECT for chronic pain patients, with variable results. This literature is reviewed and clinical recommendations are provided for ECT in such patients. Additionally, possible neurobiologic mechanisms are discussed.

Key words: Electroconvulsive therapy; Chronic pain; Primary pain syndrome; Primary depression syndrome; Neurobiologic mechanisms

Address correspondence to Keith G. Rasmussen, M.D., Mayo Clinic Department of Psychiatry and Psychology, 200 First St. SW, Rochester, MN 55905. Tel: (507) 284-3789; Fax: (507) 284-4158; E-mail: rasmussen.keith@mayo.edu




Reviews in Analgesia, Vol. 7, pp. 69-82
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Opioid Research in Amphibians: A Unique Perspective on Mechanisms of Opioid Analgesia and the Evolution of Opioid Receptors

Craig W. Stevens

Department of Pharmacology & Physiology in the College of Osteopathic Medicine, Oklahoma State University-Center for Health Sciences, Tulsa, OK

This review summarizes the work from our research group investigating mechanisms of opioid analgesia using the Northern grass frog, Rana pipiens. Over the last dozen years, we have accumulated data on the characterization of the behavioral effects after opioid administration, on radioligand binding studies using opioid agonist and antagonist ligands bound to amphibian brain and spinal cord homogenates, and by cloning and sequencing opioid-like receptor cDNA from amphibian CNS tissue. Relative analgesic potency of mu, kappa, and delta opioids is highly correlated between rats and frogs. Behavioral and binding studies using selective antagonists are not selective in amphibians. Three opioid-like receptor cDNAs were sequenced and are orthologs to mammalian mu, kappa, and delta opioid receptors. Phylogenetic analysis of the three types of opioid receptor cDNAs from all vertebrate species with full data sets gave a pattern of the molecular evolution of opioid receptors marked by divergence of mu, kappa, and delta opioid receptor sequences during vertebrate evolution. The order of receptor-type evolution is kappa, then delta, and most recently the mu opioid receptor. Finally, analyses suggest that conserved receptor domains determine the type selectivity of vertebrate opioid receptors.

Key words: Amphibians; Opioid analgesia; Opioid receptors; Rana pipiens

Address correspondence to Craig W. Stevens, Ph.D., Professor of Pharmacology, OSU-Center for Health Sciences, College of Osteopathic Medicine, 1111 W. 17th Street, Tulsa, OK 74107-1898. Tel: (918) 561-8234; Fax: (918) 561-8276; E-mail: scraig@chs.okstate.edu




Reviews in Analgesia, Vol. 7, pp. 83-96
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Copyright © 2003 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Modulation of Guanosine-5'-O-(3-[35]thio)triphosphate ([35S]GTP-g-S) Binding by Opioid Agonists and Antagonists

Heng Xu and Richard B. Rothman

Clinical Psychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224

The development of the [35S]GTP-g-S binding assay has proven to be a valuable tool for studying opioid receptor mechanisms. In addition to being useful for medicinal chemistry applications, where it is important to determine if a compound is an agonist or an antagonist, this assay has provided new insights into the mechanisms of opioid tolerance and dependence. Importantly, this assay can provide a new dimension to structure-activity studies. The main purpose of this article is to review the recent work in our laboratory that used the [35S]GTP-g-S binding assay to advance our understanding of the four parameters associated with ligand-receptor interaction: potency, efficacy, intrinsic efficacy, and binding affinity, as well as molecular mechanisms associated with opioid tolerance and dependence. A major finding to emerge from our research is that the structure-activity of intrinsic efficacy is different from the typically studied structure-activity of binding affinity. The relative ease of determining the intrinsic efficacy of a compound with the [35S]GTP-g-S provides a simple approach to develop novel opioid ligands as both pharmacological tools and potential therapeutic agents.

Key words: [35S]GTP-g-S; Morphine; Tolerance; Dependence

Address correspondence to Richard B. Rothman, M.D., Ph.D., CPS, IRP, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. Tel: (410) 550-1487; Fax: (410) 550-2997; E-mail: rrothman@intra.nida.nih.gov