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Redefining the Search for the Magic Bullet

Pain research has been enriched by remarkable discoveries during the past three decades leading to an unprecedented understanding of underlying mechanisms.

Ronald Dubner(rdubner@the-scientist.com)
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Pain research has been enriched by remarkable discoveries during the past three decades leading to an unprecedented understanding of underlying mechanisms. But in spite of these discoveries, little has been translated into effective pain therapy. Pain research should take a page from cancer research. Instead of searching for a single drug panacea, we should dwell on the differences in pain conditions and pursue multiple treatment approaches. There will not be one magic bullet for all pains. Rather, to effectively characterize and treat the broad spectrum of pain experiences, we will need to take advantage of the latest technical approaches in genomics and proteomics.

For those of us following the field, the discoveries have been nothing short of breathtaking. Specialized receptors that signal the presence of tissue damage have been identified in skin, viscera, and other tissues; and molecular biology tools have been used to clone them. We have learned that...

LACK IN TRANSLATION

One might think that such remarkable discoveries would herald a tremendous pharmacopoeia and various new approaches for pain treatment. But this is not the case. We still rely almost completely on three classes of compounds that have been available for many decades: aspirin-like drugs, local anesthetics, and morphine-like drugs. Although these satisfactorily treat acute or transient pain, they either lack efficacy or have undesirable side effects in the treatment of persistent or chronic pain.

The inability to translate research advances from bench to bedside has been very disappointing. And of the possible explanations for this stagnation, a major one is the continued search for a magic bullet. The public desires a potion to eliminate all types of pain. The pharmaceutical industry has spent millions of dollars searching for a blockbuster of a drug to relieve pain. And doctors and scientists want to help patients in the simplest way possible. But there is no magic bullet for all pains. Persistent or chronic pains are distinct in their signs, symptoms, and underlying mechanisms. And the complex pain experience involves multiple dimensions.

Pain comes with its own neural apparatus to code the intensity, quality, temporal, and spatial aspects of a tissue-threatening or damaging stimulus. It certainly captures our attention, but has different meanings for different people, producing anxiety, fear, stress, and other negative feelings depending on the previous experiences of the sufferer. It alters the quality of life. Such psychological aspects of the pain experience alone make it unlikely that a single agent with specific action at target sites in the nervous system will relieve all pains. Neither a single treatment nor a single mechanism will be sufficient.

Thus, we need a paradigm shift in our approach to the study of the mechanisms and treatment of pain. The fight against cancer might inform such a shift. Just like different cancers, chronic or persistent pain conditions have unique gene and protein profiles. In addition, the definition of many of these pain conditions can also be characterized clinically. The correlation of the genetic signature of a particular pain with its quantitative sensory signature may prove to be a powerful way to analyze the uniqueness and individuality of pain experiences. In a similar fashion, each patient's genetic background may reveal unique differences in gene and protein expression that define a unique level of susceptibility to pain and analgesics.

THE NEXT STEP

Innovative research has brought us a long way, but now we need to take the next step in moving toward the genomics of pain. We have learned that there are multiple target sites in the peripheral and central nervous system where pain can be attacked. There are a multitude of specialized receptors in skin and other tissues that signal chemical, thermal, and mechanical changes associated with pain. We know from experience that targeting only one of them will not work because of the redundancies that exist in their activation; blocking the actions of any one of them will likely lead to compensatory effects in others. This is especially true with the transient receptor potential proteins, the acid sensing ion channels, and other receptors. To effectively control pain, one would need a cocktail of receptor blockers that would require development and testing of effective agents for each. Such an approach is obviously not viable financially.

In contrast, targeting mechanisms that are at sites of convergence of input from multiple receptors in the periphery may be more effective. Sodium channels are such a site, particularly the tetrodotoxin (TTX)-resistant sodium channels that are present exclusively in peripheral nociceptive afferents. One problem here is that a multitude of similarly structured sodium channels exist, and it has proven difficult to develop an analog that blocks one exclusively. Furthermore, an analgesic acting at TTX-resistant sodium channels assumes that the pain originates in the periphery and that its maintenance requires ongoing input. This is likely not the case with at least some chronic or persistent pain disorders.

Again, it appears that a cocktail that reaches a combination of mechanistic targets will be necessary. A best approach to determining the effectiveness of a cocktail will be to study how it alters the gene-expression and sensory signatures of a given pain condition. Combining genetic signatures with pharmacological manipulations sounds very much like the pharmacogenetics approach to cancer, but with an important added wrinkle: the quantitative sensory and psychological components of different persistent pains.

Another site of converging input from multiple peripheral tissue receptors are the glutamate receptors in the spinal cord and their homologs in the trigeminal system. The N-methyl-D-aspartate (NMDA) receptor is such a target because it is uniquely activated by persistent input. And agents that block the NMDA receptor do not alter responses to transient protective pain. The problem here has been the ubiquitous nature of this receptor. Glutamate is the major transmitter in the nervous system, and NMDA receptors are integral components at sites of neuronal plasticity. This includes higher centers in the cerebral cortex and elsewhere. Therefore, the blocking of NMDA receptors can have generalized side effects.

Further research will hopefully lead to a recognition of differences in NMDA receptor function at different neuronal sites, and combining such knowledge with new and selective delivery methods such as siRNA or antisense technology could lead to effective pain pharmacogenetics. Downstream from the NMDA receptor are cellular messengers such as protein kinases, which play important roles in gene transcription and receptor phosphorylation. Receptor phosphorylation is a critical component of neuronal plasticity, contributing to changes in sensitivity of the NMDA receptor, among others. Gene transcription can enhance the sensitization process at the spinal level and elsewhere. Blocking the action of specific protein kinases can reduce the amplification and persistence of pain by altering gene and protein expression. Gene and protein profiling will begin to play a larger role in monitoring such changes.

A MODEL FOR THE FUTURE

To date, much of our understanding on mechanisms of pain has evolved from the development of tissue and nerve injury animal models of persistent pain. While these models rarely mimic clinical pain conditions perfectly, the findings can often be translated to an understanding of pain mechanisms in humans. Beyond this, however, animal models have often proven to be effective predictors of analgesic efficacy. The anticonvulsant, gabapentin, and the calcium-channel blocker, ziconitide, both appeared effective in animal models of nerve injury and have been shown to be useful in the treatment of neuropathic pain. The pain field can take advantage of these animal models and determine their genetic and sensory signatures. To improve modeling, an early step in drug discovery should be the use of the genetic and sensory profile of an animal model of inflammation or nerve injury and its susceptibility to analgesic manipulation. By comparing such genetic changes in animals with human pain conditions, we can identify the best models for specific conditions as well as the best drugs for different pains. Rather than a single panacea, such work might lead to an arsenal of more limited but more effective treatments.

The clinical ineffectiveness of some individual transmitters and receptors that showed great promise in animal models teaches us a lesson. Targeting single chemical mediators and single sites in nociceptive pathways is not the answer for drug discovery. Recent advances in microarray gene and protein profiling and clinical pain measurement allow us to examine the susceptibility of the nervous system to different persistent pain conditions and different analgesic agents and to correlate them across multiple outcome measures. It also may provide information on individual patient susceptibility to pain and analgesia. The future magic bullet won't be an all-powerful drug, but rather our ability to identify the unique profiles of different persistent pains and their relative sensitivity to a host of new therapeutic approaches.

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