Glial cell line–derived neurotrophic factor (GDNF) family ligand (GFL) consists of GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). These GFLs signal through a receptor complex consisting of coreceptor (GFRα1–4) as a ligand binding component, which has no intracellular domain and is anchored to the plasma membrane with glycosylphosphatidylinositol, and the transmembrane RET (rearranged during transfection) receptor tyrosine kinase as a signaling component. These GFRαs define ligand specificity: GDNF binds to GFRα1, NRTN to GFRα2, ARTN to GFRα3, and PSPN to GFRα4 with high affinity. Small dorsal root ganglion (DRG) neurons have been classified with binding property to plant lectin IB4, and majority of IB4–binding DRG neurons express RET. In rats about 80% of IB4–binding nociceptive DRG neurons express either GFRα1, or GFRα2, or both.

GDNF sensitizes nociceptors to mechanical and thermal stimuli when injected into the skin, and also sensitizes muscle nociceptors to mechanical stimulus when injected to the muscle, inducing behavioral mechanical hypersensitivity. Authors’ group showed that GDNF produced by muscle cells ⁄ satellite cells plays a pivotal role in mechanical nociceptive hypersensitivity after exercise (delayed onset muscle soreness). In experimentally induced inflammation, GDNF, NRTN and ARTN, and their receptors GFRα1, 2 and 3 are involved in nociceptive hypersensitivity. In contrast to inflammatory pain, intrathecally injected GDNF induces analgesia in neuropathic painful conditions. Clinical usage of GDNF for the treatment of neuropathic pain is not feasible because of side effects such as body weight loss and allodynia.

In this review we introduce that mixture of low dose NGF and GDNF, which by themselves do not induce mechanical hypersensitivity of the muscle, induces statistically significant decrease of muscular mechanical withdrawal threshold (muscular mechani­cal nociceptive hypersensitivity). The mixture also increases pERK immunoreactivity in DRG neurons responding to mechanical stimulation, suggesting that collaborative interaction of NGF and GDNF occurs at the level of primary afferents. For the basis of this collaborative interaction, colocalization of their receptors TrkA and GFRα1 in lumbar dorsal root ganglia is introduced. In addition, production of receptor for brain derived neurotrophic factor (BDNF) are introduced, then its role in pain in pathological conditions such as inflammation and nerve injury, and a possible role in exercise induced analgesia is also introduced. Finally spinal mechanism of nociceptive hypersensitivity induced by BDNF is introduced with special emphasis on the role of K⁺–Cl^– cotransporter KCC2.

Pain behavior observation is recommended for pain assessment in the elderly with dementia. Pain behavior observation may be useful not only in patients with dementia but also those with cognitive impairment in general. However, the characteristics of pain behavior may differ depending on the degree of cognitive decline. This study examined the characteristics of pain behavior using the verbal rating scale (VRS) and the Abbey pain scale (APS) in elderly adults with mild cognitive impairment (MCI) and dementia.

This study enrolled 199 participants with MCI (n=41) and dementia (n=158). VRS and APS were used to assess the patient’s pain during walking or transferring by one assessor. VRS and APS were compared in both groups. The kappa coefficient was calculat­ed to determine the degree of agreement between VRS and APS. The item response theory was used to analyze the APS items and extract variables that reflect the presence of pain.

There were no significant differences in the demographic data, VRS, or APS between the two groups. The kappa coefficient was 0.109 (p=0.387) for the MCI group and 0.282 (p<0.001) for the dementia group. Using the item response theory, "Vocalization", "Facial expression", and "Change in body language" were commonly identified as characteristics of pain behavior in both patients with MCI and those with dementia.

The results indicated that among elderly adults with MCI, there are discrepancies between self–reported and observed pain behaviors. The results suggest that for the elderly with suspected cognitive decline, a combined assessment of pain behavior observation and patient–reported outcomes, such as VRS, is recommended. Moreover, pain assessment that focuses on the three behaviors of "Vocalization", "Facial expression", and "Change in body language" may improve pain assessment in elderly patients with cognitive decline.

We experienced a case in which treatment with traditional Chinese herbal and acupuncture successfully reduced pain and increased the quality of life. A woman in her 90s had a herpes–zoster 7 years ago, and developed chronic postherpetic neuralgia (PHN). She underwent nerve block therapies several times, but they were ineffective. When we started to treat, she was taking a low dose of pregabalin. Her pain score of visual analogue scale (VAS) was 100 mm. We evaluated the effect of our treatment by VAS score and SF–8 acute version for 6 months. We treated her with keishikajutsubuto extract granules, a frequently used remedy for neuralgia aggravated by cold. Acupuncture treatment was executed once a week. The VAS score dropped to 17 mm and the intense pain that struck her several times a day was drastically reduced after 6 months treatment. Physical function– and mental health–related parameters from the SF–8 analysis were also improved. Despite a very elderly woman with many comorbidities and refractory PHN seven years after the onset of the disease, it was possible to reduce her pain and improve her quality of life by the addition of oriental medicine such as Chinese herbal medicine and acupuncture, while continuing conventional western medical treatment.