Hyperalgesia and amino acids. Receptor selectivity based on stimulus intensity and a role for peptides

The reader may have noted that we have tried to restrict our discussion to mechanisms of cutaneous hyperalgesia. We have taken the liberty to include some discussion of hyperalgesia produced by inflammation of deeper tissues and articular spaces since these conditions appear to share many mechanisms in common with cutaneous hyperalgesia. We have carefully avoided a discussion of the mechanisms underlying hyperalgesia produced by injury to viscera or nervous tissue because space constraints do not permit us to address the special issues that pertain to these conditions. Dr. Meller's thesis outlines an interesting new perspective on the chemical mechanisms of hyperalgesia. Although the widely accepted preexisting intensity-based hypothesis may not yet account for all aspects of hyperalgesia, it does account for a large body of psychophysical data as well as experimental data that has been gathered from study of the dorsal horn alone. It is not at all clear that this previously established hypothesis has been refuted, or that Dr. Meller's alternate hypothesis better accounts for this same body of information. Finally, we have avoided commentary on the potential role of second messenger systems and gene expression modifications that may be involved in the generation-expression of hyperalgesia given the complexity of the neurotransmitter mechanisms. Dr. Meller should be applauded for the service he does indicating the multiplicity in second messenger systems that may potentially be involved. However, his scheme will likely require extensive modification. Allowances need to be made for the messenger systems of the neuropeptides and for the issue of multiplicity in the mechanisms for expression-maintenance of hyperalgesia. For example, a recent publication by Minami et al.⁶¹ illustrates that interactions between cyclooxygenase products and excitatory amino acids can involve either of the excitatory amino acid receptor subtypes. Thus, this final issue, as well as the role of gene expression changes, will no doubt be an area of research increasingly addressed in many future studies.