ognizant Communication Corporation

(formerly ANALGESIA)


Reviews in Analgesia, Vol. 7, pp. 97-117
1542-961X/04 $20.00 + .00
Copyright © 2004 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Critical Evaluation of Reported Plant Sources of Possibly Novel Analgesic Compounds

Navneet Bassi, Andrea R. Cohen, Shyam Desai, Manuel G. Espinosa, Erin E. Flynn, Keith E. Franchetti, Anupama Kuriakose, Stephany-Kieu T. Lam, Kin S. Ly, Michael J. McGraw, Niloufar N. Namazi, George A. Nemeh, Cynthia D. Oliva, Sonak D. Pastakia, Kathleen M. Riley, Oluwatosin A. Tairu, and Robert B. Raffa

Temple University School of Pharmacy, Philadelphia, PA

A recent publication summarizes the results of a literature search that identified over 200 plants--belonging to more than 70 families found in different parts of the world--that have putative antinociceptive activity in preclinical tests. It is claimed that all of the species (extracts) appear to produce their antinociceptive activity through "opioidergic receptors." Such information is extremely valuable, particularly if substances of novel opioid structure or characteristics are discovered. We examined the original articles on 60 of the plants and classified them based on: (1) evidence of antinociceptive activity in the absence of confounding behavioral or toxic effects, and (2) evidence of an opioid mechanism. While the results of almost all of the studies offer interesting leads, nine studies report unequivocal opioid-linked antinociception based on naloxone reversal or radioligand binding data. The structures of four novel putative opioid substances are presented. In addition, interesting novel structure-activity relationships are suggested for the opioids and nonopioids. All of the studies provide novel and fertile material for basic and applied analgesic research.

Key words: Analgesia; Antinociception; Plants; Opioid; Preclinical tests

Address correspondence to Robert B. Raffa, Ph.D., Temple University School of Pharmacy, 3307 N. Broad St., Philadelphia, PA 19140. Tel: (215) 707-4976; Fax: (215) 707-5228; E-mail: robert.raffa@temple.edu

Reviews in Analgesia, Vol. 7, pp. 119-128
1542-961X/04 $20.00 + .00
Copyright © 2004 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Protein Kinases and Persistent Pain States

Karla P. Zeitz and Annika B. Malmberg

Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080

Injury-evoked persistent pain is mediated by changes in nociceptive processing in both the peripheral and central nervous systems. Although many mechanisms have been implicated in the induction and maintenance of the changes underlying persistent pain, it is clear that the activation of membrane receptors and the subsequent stimulation of protein kinase activity are critical for sustained alterations in neuronal activity. From a functional perspective, early studies using pharmacological agents of unspecified selectivity identified major kinase families involved in injury-induced behavioral changes. More recently, it has been possible to use tools such as subtype/isoform-specific knockout mice, enzyme-specific peptide inhibitors, and selective markers of kinase activity to characterize the contribution of particular kinase isoforms to persistent pain. The identification of specific kinase family members involved in the generation and maintenance of injury-evoked pain may prove useful in the development of new therapeutics for the treatment of persistent pain.

Key words: Persistent pain; Peripheral sensitization; Central sensitization; Injury, Kinase

Address correspondence to Annika B. Malmberg, Ph.D., Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080. Tel: (607) 794-4253; Fax: (650) 877-7486; E-mail: Annika.Malmberg@elan.com

Reviews in Analgesia, Vol. 7, pp. 129-143
1542-961X/04 $20.00 + .00
Copyright © 2004 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Placebo-Induced Analgesia: Methodology, Neurobiology, Clinical Use, and Ethics

Fabrizio Benedetti and Luana Colloca

Department of Neuroscience, Clinical and Applied Physiology Program, University of Turin Medical School, Turin, Italy

Striking placebo effects can be observed in different circumstances, provided that the appropriate methodological approaches and control groups are used. These effects are due to conscious anticipatory processes and/or to unconscious mechanisms of conditioning. Placebo-induced analgesia is mediated by an endogenous pain-modulating system descending from the limbic cortex to the brainstem and involving endogenous opioids. This endogenous opioid system acts not only on pain transmission but also on the respiratory centers and the sympathetic nervous system. Due to several ethical constraints, the use of placebos in both clinical trials and routine medical practice is controversial. However, these ethical limitations can be partially overcome by considering that a placebo procedure can reduce the intake of some drugs, like narcotics. In addition, a new paradigm, which is based on open versus hidden administrations of drugs, can be used to reveal and investigate the placebo component of a therapy without administering any placebo.

Key words: Placebo effect; Nocebo effect; Opioid systems; Endogenous pain modulation; Psychosocial context; Placebo-controlled trials; Therapist-patient interaction

Address correspondence to Fabrizio Benedetti, M.D., Dipartimento di Neuroscienze, Università di Torino, Corso Raffaello 30, 10125 Torino, Italy. Tel: +39 011 6707709; Fax: +39 011 6707708; E-mail: fabrizio.benedetti@unito.it

Reviews in Analgesia, Vol. 7, pp. 145-163
1542-961X/04 $20.00 + .00
Copyright © 2004 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The Formalin Test: Characteristics and Usefulness of the Model

Jana Sawynok1 and Xue Jun Liu2

1Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7
2University of Toronto, Hospital for Sick Children, Brain and Behavior, McMaster Building, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

The formalin test was introduced as a model of tonic pain in 1977, and has since been used extensively in rats and mice. In rats, formalin generates an initial phase of activity (5-10 min, phase 1), a quiescent interphase (5-10 min), and a second phase of activity (lasting 60-90 min, phase 2), and this is seen with spontaneous behaviors, firing of afferent neurons, and activity in dorsal horn neurons. Both active phases involve ongoing peripheral afferent neural activity; inflammation contributes to phase 2 activity and the interphase results from active inhibition. Responses are concentration dependent between 0.25% and 2.5%, plateau from 2.5% to 5%, and can decline at higher concentrations. Formalin also results in tissue edema, and this is longer lasting. Responses to formalin up to 2.5% are predominantly neurogenic, while at higher concentrations, responses involve a further prominent inflammatory component. Within the spinal cord, formalin increases c-Fos expression in neurons and causes activation of microglia, and these may contribute more prominently to longer term changes. Acute responses (to 90 min) may represent a model of ongoing acute pain involving inflammation and aspects of central sensitization, while longer term responses (days, weeks) may represent a model of changes involved in persistent pathological pain.

Key words: Formalin test; Pain model; Phase activity; Peripheral afferent neural activity; Central sensitization; Acute responses; Long-term responses

Address correspondence to Jana Sawynok, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. Tel: (902) 494-2596; Fax: (902) 494-1388; E-mail: jana.sawynok@dal.ca