This review introduces the roles of nerve growth factor (NGF) in musculoskeletal pain such as osteoarthritis (OA), chronic low back pain (CLBP) and delayed onset muscle soreness. Both animal and human studies are included. In addition, therapeutic perspectives of anti–NGF antibody in treatment of bone cancer pain, OA pain and CLBP was briefly introduced.
We focus in the present review on the molecular mechanisms for nerve growth factor (NGF) to induce thermal ⁄ mechanical hyperalgesia. Transient receptor potential vanilloid 1 (TRPV1) is pivotal to sensitize nociceptor to heat after NGF administration. Acceleration of membrane trafficking of TRPV1 through protein kinase C pathway without increase in gene expression contributes acute thermal hyperalgesia. Signaling endosome of NGF–receptor tyrosine kinase A (TrkA) complex is transported from peripheral axonal terminal to the cell body and activate transcription factors. This transcriptional activation causes upregulation of some sodium channels, neuropeptides and acid–sensing ion channels to induce long–lasting sensitization to heat. Histamine and serotonin released from activated mast cells and neutrophils by NGF also indirectly contribute to inducing thermal hyperalgesia.
NGF also causes mechanical hyperalgesia in not only animals but also human. Repetitive administration of NGF induces long–lasting and wide–spreading mechanical hyperalgesia, that is reduced by TrkA signaling pathway inhibition. Recent report demonstrates NGF and Piezo2 are involved in mechanical sensitization of the silent nociceptor. However, mechanism of mechanical sensitization by NGF is still unclear, as mechanical transducer channels are not fully identified in other nociceptors. We hope molecular mechanism in NGF–induced hyperalgesia will be clarified in the future.
An approach of multidisciplinary pain treatment is one of the useful methods for the treatment of chronic musculoskeletal pain because of its therapeutic effectiveness, cost–effectiveness, and smallness of iatrogenic complications. We are implementing a multidisciplinary pain treatment using a 3–week inpatient program based on the biopsychosocial model guided by the International Association for the Study of Pain (IASP) recommendations for such a program in Fukushima, Japan.
We performed the multidisciplinary inpatient pain management program for the 28 patients (10 male and 18 female) with chronic musculoskeletal pain from April 2015 to July 2021. Twenty–eight patients were classified two types by the International Classification of Diseases 11th Revision J (ICD–11J) as below; 1) 12 patients (4 male and 8 female) with chronic primary pain, and 2) 16 patients (6 male and 10 female) with secondary musculoskeletal chronic pain.
The purpose of this study was to examine the therapeutic effect of the multidisciplinary inpatient pain management program for 28 patients with secondary musculoskeletal chronic pain or chronic primary pain.
We evaluated 1) the degrees of pain using brief pain inventory (BPI), 2) the psychosocial factors in pain using pain catastrophizing scale (PCS) (rumination, magnification, and helplessness), pain disability assessment scale (PDAS), hospital anxiety and depression scale (HADS), pain self–efficacy questionnaire (PSEQ), and 3) Quality of life (QOL) using the EuroQol Five Dimensions Questionnaire (EQ–5D) and the Athens Insomnia Scale (AIS). Statistical analyses were performed using Wilcoxon matched–pairs signed rank sum test. We considered p–values less than 0.05 to be statistically significant in the variance analyses.
Comparing results before and after the program, the following statistically significant improvement in both patients with secondary musculoskeletal chronic pain and chronic primary pain were seen in PCS (magnification, helplessness, total), PDAS, HADS (anxiety, depression), PSEQ, EQ–5D. The following statistically significant improvement in only the patients with chronic primary pain were seen in BPI (p=0.017). On the other hand, the following statistically significant improvement in only the patients with secondary musculoskeletal chronic pain were seen in PCS (rumination) (p=0.032) and AIS (p=0.022).
We concluded that it would be possible to predict the therapeutic effect of the multidisciplinary inpatient pain management program broadly if the patients with chronic musculoskeletal pain were classified the pain type using ICD–11J before treatment.
In order to educate employees, managers, and occupational health professionals in companies throughout Japan about appropriate knowledge and information about chronic pain, we created the "Chronic Pain Prevention E–Learning". Three courses have been established: one for e–occupational health staff, one for managers, and one for employees. The course for occupational health staff and managers includes content such as the significance of chronic pain countermeasures and how to balance treatment and work. The course for employees includes content such as self–care. The number of applicants was limited to 6,000, and there was no course fee. The number of participants was 3,806 (320 in the occupational health staff course ⁄ 946 in the management course / 2,540 in the employee course), with 190 participating companies and organizations, and the overall completion rate was approximately 40%. More than 80% of participants in all courses indicated that they were satisfied with the content. Surveys using stress checks, which are mandatory for companies, have shown that many high–stress individuals complain of chronic pain. The key to raising awareness and disseminating appropriate knowledge about chronic pain in companies is how to gain the understanding of not only the medical profession, but also management and HR personnel.
Delayed onset muscle soreness (DOMS) is defined as pain or mechanical hyperalgesia induced after unaccustomed strenuous muscular work, including lengthening contractions (LC), yet the molecular mechanism is largely unknown. Recently, TACAN (also referred to as Tmem120a) has been reported as an ion channel involved in sensing mechanical pain (Beaulieu–Laroche et al., Cell, 2020) and mechanical hyperalgesia after inflammation in the skin (Bonet et al., J Pain, 2020). However, the role of TACAN in DOMS is unknown. Here we examined the expression profiles of TACAN mRNA in the muscle using a rat model of DOMS. Under isoflurane anesthesia, male Sprague–Dawley rats (aged 9–12 weeks, weighing 295–397 g) were exposed to repetitive LC of the lower leg extensor muscles [mainly tibialis anterior (TA) muscle]. Shallow and deep layers of the TA were sampled 24 h after LC, when mechanical hyperalgesia reaches at its peak after LC (Hayashi et al., Eur J Pain, 2017). The expression level of TACAN and nerve growth factor (NGF) mRNA was measured using real–time RT–PCR. In the shallow layer of the TA, the TACAN and NGF mRNA level were significantly increased on the ipsilateral side of LC, compared to the contralateral side. In the deep layer of the TA, the expression level was unchanged. These results suggest that TACAN upregulated in the shallow layer of the muscle that underwent LC is involved in the generation of mechanical hyperalgesia in DOMS.