Dear Colleagues,

Growing numbers of molecules have been suggested to contribute to the development of chronic inflammatory or neuropathic pain. Based on rodent models, some of these molecules have potential as drug targets, such as fatty acid amide hydrolase, which regulates the metabolism of endocannabinoids, and GTP cyclohydrolase, which is the key enzyme in tetrahydrobiopterin synthesis. However, so far, no compounds have reached clinical practice and patients have few therapeutic options. No matter the reason for the pain, treatment focuses on symptom relief, but does not address or cure the underlying pathology of pain signaling. Available therapeutics either target opioid and cannabinoid receptors or cyclooxygenases or nonspecifically lower neuronal excitability. Pain relief via these drugs is associated with side effects. Therefore, there is still a high clinical need for novel pain-therapeutics that would address the underlying causes. Thus, there is a continuing search for targetable molecules and cellular processes, such as neuronal death. Also, there is continuing research concerning the interplay of neurons, glial cells, and immune cells. One approach is the targeting of activated (micro)glia for treatment of neuropathic pain because these cells produce pro-inflammatory substances, which maintain hyperexcitability in nociceptive neurons, even if the nerve injury is healed. The glia activation is driven by, e.g., specific purine receptors, cytokines, and growth factors, and are inhibited by inflammation resolving lipid signaling molecules, which are all potentially interesting drug targets. Transient receptor potential channels and specific sodium channels are long known as key molecules for nociception and there are some intelligent drugs that enter through one channel and then target the other from inside (to confer some specificity). However, successful pain reduction in rodents only moderately predicts efficacy in humans, because the pain goes far beyond nociception and behavioral tests in rodents rely mostly on the stimulation of an inflamed or nerve injured paw, but do not measure spontaneous pain or long-term adaptive changes in pain-associated centers. Thus, pain-causing or pain-resolving molecules must be seen in a broader context of pain as a systemic disease.

Prof. Dr. Irmgard Tegeder
Guest Editor

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• microglia
• neuronal apoptosis
• purine receptors
• TRP channels
• cytokines
• hyperexcitability
• cannabinoids
• opioids
• lipid signaling molecules