Owing to improvements of medical technology, cancer has become a treatable disease. While the number of cancer survivors is gradually increasing year by year, many patients are suffering from pain as side–effects or after–effects of cancer treatment. Opioids are used as medical narcotics for the treatment of cancer pain. In the United States, opioid prescriptions that prioritize pain relief have led in many cases to opioid addiction and abuse, and many patients have lost their lives due to overdoses of opioid analgesics. There is an urgent need to develop new methods to reduce the use of opioids and novel effective treatments with fewer side–effects to overcome this situation. Endothelin, known as a vasoconstrictor, has been shown to be involved in pain through its specific receptor, the endothelin A receptor. In addition, endothelin A receptor antagonists are also known to potentiate the effects of opioids and relieve opioid tolerance, although the mechanisms are yet to be elucidated. Here, we present a review based on previous reports on the relationship between endothelin–associated pain signaling and opioids. Furthermore, we show that heterodimerized endothelin A and μ–opioid receptors are involved in endothelin A receptor–mediated pain. We also show that a novel endothelin A receptor antagonist with a higher selectivity for the endo­thelin A receptor than existing endothelin A receptor antagonists, potentiates opioid effects; this endothelin A antagonist would potentially be a novel analgesic adjuvant.

On the way of analyzing the mechanism of delayed onset muscle soreness, author’s group found that nerve growth factor (NGF) and glial cell line derived neurotrophic factor (GDNF) synergistically interact to induce muscular mechanical hyperalgesia. However, it is believed that NGF and GDNF work on different sets of DRG neurons that express NGF receptor, TrkA or GDNF receptor, GFRα1–RET. However, this result was obtained from skin–innervating neurons or whole DRG neurons. It is not known whether muscle innervating DRGs are similar. In this experiment we examined whether it is also true for muscle innervating DRG neurons. We identified muscle innervating DRG neurons using retrograde tracing with Fluoro–Gold. Under anesthesia FG (4%, 10 µl) was injected to 10 points each of medial and lateral head of gastrocnemius muscle (GC). Ten to eleven days later rats were perfused and fixed under deep anesthesia. Using serial sections immunohistochemistry for FG and double in situ hybridization for TrkA and GFRα1 were performed. As a result 39%–50% of FG+ DRG neurons were TrkA+, and 69–77% were GFRα1+. Co–expression of TrkA and GFRα1 was observed in 24%–29% DRG neurons innervating GC. The size distribution of FG + DRG neurons did not show a skewness in small size range (< 600 µm²), rather distributed equally in small to large cell ranges. Size distribution of TrkA+ neurons and double positive (TrkA+ and GFRα1+) also showed no skewness in small size range and distributed widely from small to large size. A part of these TrkA+ ⁄ GFRα1+ coexpressing neurons might be the site of synergistic interaction of NGF and GDNF.

In recent years, numerous studies have reported the clinical utility of Japanese herbal medicines for pain diseases, and their demand is increasing. However, it is difficult to conduct basic research on these medicines because Japanese herbal treatments are multi­component systems, composed of herbal medicines with multiple actions. Hence, scientif­ic elucidation of their pharmaceutical mechanisms is complicated.

Here, we have outlined studies indicating the use of on Goshajinkigan (GJG) in relieving neuropathic pain. Furthermore, efforts have been made to elucidate the underly­ing analgesic mechanisms. Basic research on GJG has primarily explored strepto­zotocin–induced diabetic neuropathy models and chemotherapy–induced neuro­pathy models. We have demonstrated that GJG is also valuable in the choronic constrictive injury (CCI) models and that its analgesic mechanism is the inhibition of activated microglia–derived tumor necrosis factor–alpha in the spinal dorsal horn. Scientific elucida­tion of the analgesic mechanisms of Japanese herbal medicines may lead to the establishment of new uses and indications for these treatments fused with modern medicine and may be a great help in the treatment of refractory neuropathic pain that is prone to becoming chronic pain.

Transient receptor potential (TRP) ion channels form a family of ligand–gated ion channels that function as molecular detectors of physical stimuli, including light, tempera­ture, chemical and mechanical stimuli. Several TRP channels including TRPV1, TRPA1 and TRPM8 are expressed by nociceptors and play crucial roles in sensation of pain. Recently, several traditional herbal medicines (Kampo medicines) have attracted attention due to their excellent effects on management of pain in clinic. Many ingredients of these Kampo medicines could activate or inhibit TRP channels, which indicates involvement of TRP channels in analgesic action of the Kampo medicine. This review focuses on the increasing evidence of TRP channel modulation by natural compounds and try to find the molecular mechanism of Kampo medicine in treating pain disease.

Although the number of needed to treat (NNT) for pharmacotherapy is less than three in patients with acute pain, it is reportedly three or higher in patients with neuropa­thic pain. That might be caused partly by large differences in patients’ characteristics, genetics, and psychosocial factors, in addition to individual differences in pain mechanisms, pharmacokinetics, and pharmacodynamics in neuropathic pain. Therefore, an individualized pharmacotherapy is crucial for better analgesic effects for neuropathic pain. Previous studies using the quantitative sensory testing (QST) reported that neuropathic pain characteristics are classified into three mechanistic subgroups: sensory loss with deafferentation, thermal hyperalgesia with peripheral sensitization, and mechanical hyperalgesia with central sensitization. Pain symptoms described in the neuropathic pain symptom inventory (NPSI) were also divided into three sensory phenotypes of pinpointed pain, evoked pain, and deep pain. Analgesic efficacies of each drug were reportedly different in each group. Other analysis methods using psychological, chemical, and genetic characteristics also have been examined to individualize the analgesic effects on neuropathic pain. Further investigations, however, are still needed to develop an individualized pharmacotherapy reducing the NNT in patients with neuropathic pain.

Central sensitization (CS) is defined as an increased responsiveness of nociceptive stimuli caused in the central nervous system (CNS), and is widely used to explain hypersensitivity, pain to non–noxious stimuli (allodynia), and expanded painful area. CS is assessed by the dynamic quantitative sensory testing including temporal summation, off–set analgesia, and conditioned pain modulation. Aftersensation, which is a painful sensation remained after noxious stimuli cease, is also useful to diagnose the CS, as people with chronic pain report significantly longer aftersensation. A previous brain imaging study identified a global brain disruption associated with pain intensity in people with chronic pain. Furthermore, the mesocorticolimbic pathway, amygdala, and hippocampus were associated with predisposition of transition to chronic pain. These findings indicate a multiple–hit theory to explain a mechanism of chronic pain. Given that pain management program recovered amygdala and hippocampal volumes, treatment of the brain plasticity should be a therapeutic target in chronic pain.