PATHOPHYSIOLOGY


Abstract

The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations. Thus, placebo treatments that have no intrinsic pharmacological effects may produce analgesia by altering expectations. However, controversy exists regarding whether placebos alter sensory pain transmission, pain effect, or simply produce compliance with the suggestions of investigators. In two functional magnetic resonance imaging (FMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.

Comments: Please see comments on the above abstract, with additional comments under Migraine Treatment after the abstracts by Vickers et al and Wonderling et al.

Ion channels represent a rich and relatively untapped vein of future therapeutic targets, but realizing their potential is proving harder than first imagined. The unexpected setbacks, resulting in an ever-lengthening list of failed drug development programs based around ion channels, highlight our need for a greater understanding of the underlying biology and physiology of ion channel function. To this end, Nature Reviews Drug Discovery has attempted to survey the field by posing 20 questions of fundamental importance to the development of the field to 20 of the world's leading authorities on ion channel research, and here we present their answers.

List of questions:

  • 1What are the new technologies that are having the greatest impact on your area of ion channel research?
  • 2What tools and technologies for ion channel research would you most like to be available in the future?
  • 3How close are we to being able to integrate understanding of the cellular physiology or biophysics of ion channels with their role in disease states?
  • 4As we enter a poststructural era in voltage-gated ion channel research, what big questions remain at the structure/function interface?
  • 5How useful will molecules derived from natural sources prove to be in probing ion channel structure/function?
  • 6Biophysical and structural methods are the very opposite of high throughput. How can they be adapted to aid discovery of new lead compounds?
  • 7What, if any, will be the importance of ion channels for bionanotechnology?
  • 8Is there a bifurcation taking place in ion channel research between physiology/pharmacology and structural biology/molecular biophysics? And if so, how does one reintegrate ion channel research?
  • 9How will the sequencing of the human (and other) genomes affect ion channel research?
  • 10How might microarrays and proteomics contribute to research on ion channel diseases and/or to basic research on channel function at the single-cell level?
  • 11What are the barriers to achieving specificity using ion channel ligands?
  • 12Could there be an approach to ion channel pharmacology based around monoclonal antibodies or other biologicals, rather than small molecules?
  • 13What are the main hurdles that one would need to overcome for creating further successful therapeutic approaches based around the modulation of electrical activity?
  • 14In your opinion, what diseases are most strongly linked with aberrant ion channel function?
  • 15What are the pitfalls and advantages of animal models that seek to recapitulate the human channelopathies?
  • 16What methods are optimal for probing the correlation between genotype and phenotype in ion channel-linked diseases?
  • 17How will the almost ubiquitous expression of some ion channels affect their potential as therapeutic targets?
  • 18What would you describe as the major concerns surrounding the development of ion channel-targeting therapies?
  • 19What outstanding questions in ion channel research are likely to be sorted out in the next few years?

Comment: Twenty scientists answered these questions, and I strongly recommend this article, which can be accessed at http://www.nature.com/drugdisc/ , linked to Nature Reviews Drug Discovery. The scientists describe some of the areas of discovery and interest in ion channels, which are of such great interest in headache, due to the sodium and calcium channelopathies that cause Familial Hemiplegic Migraine (FHM). These experts list a number of advances that show great promise, including the use of x-ray crystallography and other techniques to complete the understanding of ion channel structure, the use of ion channel mutants, knock-in animals, and computer simulations to better explain function, the progress in unraveling complex genetics and the use of natural source molecules such as venoms, and exploring mechanisms of gating. “Ion channels present a multitude of opportunities for points of intervention by pharmaceutical agents.” Many targets are cited, including transient receptor proteins (TRP), G-protein-coupled receptors (GPCR), or inhibition of gating with pores. “Selectivity of drug action can be achieved by blocking, or modulating, particular states of an ion channel.” Interestingly, the scientists list some of the diseases related to ion channel dysfunction, including FHM, malignant hyperthermia, polycystic kidney disease, periodic paralysis and myotonias, cystic fibrosis, myasthenia gravis, and Long QT Syndrome (LQTS). Safety and side effects will be paramount in the development of targeted drugs, as “the ubiquitous expression of certain ion channels will limit the development of therapeutic strategies that target these channels in a specific tissue or organ.”—Stewart J. Tepper

Objective: Most research on the effects of severe psychological stress has focused on stress-related psychopathology. Here, the author develops psychobiological models of resilience to extreme stress.

Method: An integrative model of resilience and vulnerability that encompasses the neurochemical response patterns to acute stress and the neural mechanisms mediating reward, fear conditioning and extinction, and social behavior is proposed.

Results: Eleven possible neurochemical, neuropeptide, and hormonal mediators of the psychobiological response to extreme stress were identified and related to resilience or vulnerability. The neural mechanisms of reward and motivation (hedonia, optimism, and learned helpfulness), fear responsiveness (effective behaviors despite fear), and adaptive social behavior (altruism, bonding, and teamwork) were found to be relevant to the character traits associated with resilience.

Conclusions: The opportunity now exists to bring to bear the full power of advances in our understanding of the neurobiological basis of behavior to facilitate the discoveries needed to predict, prevent, and treat stress-related psychopathology.

Comments: An alert reader, Dr. Morris Maizels, sent in this reference, and it is a fascinating reading that bears on pathophysiology and neurochemistry during the stress of severe pain. —Stewart J. Tepper

Ancillary