Editorial [Hot Topic: New Frontiers in Managing Chronic Pain (Guest Editor: Gerald W. Zamponi)]

Most people will experience severe pain at some point throughout their lives. Pain can be loosely classified into “good” and “bad” pain. The former serves as a key warning system that protects us from injury. Without “good” pain, nothing would stop us from reaching into a pot of boiling oil. “Bad” pain is a form of pain that arises as a result of a chronic injury and results in persistent excitation of pain pathways. This type of pain is referred to as chronic and no longer fulfills the purpose of warning us of acute danger. Chronic pain afflicts tens of millions of Americans, however, to date, the therapeutic options remain limited and drugs that are efficacious in treating chronic pain are often associated with side effects or the development of tolerance. As a result, the drug discovery sector is actively engaged in finding novel treatments for chronic pain, and in identifying new targets. In this issue, we focus on some of the promising targets for the development of novel therapeutics to manage chronic pain. These potential targets range from voltage and ligand gated ion channels, to transporters, and G protein coupled receptors. Sodium channels are key contributors to the firing of nociceptive neurons, and persistent sodium channels have received increased attention as targets for pain treatment. Wood and Boorman highlights the role of persistent sodium channels in chronic pain, and presents a detailed overview of molecular and pharmacological aspects of sodium channel function. Voltage gated calcium channels are involved in the pain pathway in multiple ways. N-type channels are responsible for neurotransmitter release from presynaptic sites. These channels are the target of the recently FDA approved peptide drug Prialt. T-type channels regulate neuronal excitability and firing, and hence their inhibition is predicted to be antinociceptive. These developments are highlighted by Bourinet and Zamponi. Price and colleagues also exploit excitability of nociceptive neurons, but from the point of view of cation-chloride-cotransporters which are functionally coupled to GABAA receptors. Blocking synaptic transmission at postsynaptic sites may also provide an avenue for blocking nociceptive signaling. In this vein, the article by Salter focuses on protein-protein interactions involving the NMDA receptor as putative targets for regulating pain transmission at the spinal level. During inflammation, a host of proteases are released that can activate proteinase activated receptors. Cenac and Vergnolle examine the roles of protease activated receptors in the pain pathway, and suggest avenues by which these receptors might be exploited as suitable targets for analgesics. Sah and colleagues give a detailed overview of the role of neurotrophic factors in the pain pathway, and finally, the article by Cashman focuses on structure activity aspects concerning morphine-6- glucuronide analogs, a potentially novel class of analgesics. Despite tremendous activity in the area of pain research, no universal pharmacological inhibitor of pain is currently on the market. Moreover, it has remained a challenge to identify small organic, orally available molecules which are clinically active without producing side effects. Alternative avenues, may however present themselves through increased availability of gene therapies designed to depress expression of receptors and/or ion channels highlighted in this issue.