To the Editor:—

Drs. Woolf and Max should be commended for their excellent article, “Mechanism-based Pain Diagnosis.”1This article provides a rational contextual framework for the diagnosis and treatment of painful conditions, and a philosophical approach to drug discovery and evaluation. These guidelines will be indispensable for scientists developing new drugs, clinical researchers testing them, and also for clinicians, who will ultimately decide when and how to use new drugs in practice. In addition to the author's points, I would like to suggest a therapeutic focus that was not emphasized in the article, namely that of intracellular messengers conveying painful signals.

As pointed out by the authors and others, 2a wide variety of receptors and ion channels are involved in transmitting painful stimuli. It is possible that signals generated by these systems converge on a more limited set of intracellular second messenger systems. For example, previous work by Woolf has identified one such potential integrative target, the extracellular signal-related kinase (ERK) signaling cascade. 3Studies have also suggested that opioids could modulate ERK activity. 4,5Other such integrative signals have also been proposed. 6Therefore, a more parsimonious approach might be to focus on identifying changes in various intracellular signaling systems modulated in appropriate neural targets after painful stimulation. Also, potential analgesic compounds could initially be screened in in vitro  systems designed to test for blockade of specific signals. Subsequently, candidate drugs could be identified for further testing in appropriate animal models, thus minimizing animal use.

It is conceivable that such an approach may aid in the effective mechanistic classification of painful conditions, and perhaps help improve the prediction of therapeutic response to particular analgesics.

Woolf C, Max M: Mechanism-based pain diagnosis. A nesthesiology 2001; 95: 241–9
Julius D, Basbaum A: Molecular mechanisms of nociception. Nature 2001; 413: 203–10
Ji R-R, Baba H, Brenner GJ, Woolf CJ: Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nature Neuroscience 1999; 2 (12): 1114–9
Gutstein H: Opioid withdrawal activates ERK in N2A neuroblastoma cells: A potential role for ERK signaling in opioid dependence and withdrawal. A nesthesiology 2000; 93: A783
Gutstein H, Rubie E, Mansour A, Akil H, Woodgett J: Opioid effects on mitogen-activated protein kinase signaling cascades. A nesthesiology 1997; 87: 1118–26
Mao J, Price D, Mayer D: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 1995; 62: 259–74