Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.

ABSTRACT: Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent discovery of membrane bound ectopic Hsp90 (eHsp90) on tumor cells has shown that Hsp90 induction to the plasma membrane can stabilize disease-relevant proteins. Here, we characterize eHsp90 expression in a mouse model of inflammation and demonstrate its role in nociception and pain. We found that intraplantar complete Freund adjuvant (CFA) induced robust expression of eHsp90 on the cell membranes of primary afferent nociceptors located in the L3-L5 dorsal root ganglia (DRG), bilaterally, with minimal to no expression in other tissues. Complete Freund adjuvant-induced increases in eHsp90 expression on lumbar DRG were significantly greater in females compared with males. Furthermore, exogenous Hsp90 applied to primary Pirt-GCaMP3 nociceptors induced increases in calcium responses. Responses were estrogen-dependent such that greater activity was observed in female or estrogen-primed male nociceptors compared with unprimed male nociceptors. Treatment of mice with the selective eHsp90 inhibitor HS-131 (10 nmol) significantly reversed CFA-induced mechanical pain, thermal heat pain, and hind paw edema. Notably, a higher dose (20 nmol) of HS-131 was required to achieve analgesic and anti-inflammatory effects in females. Here, we provide the first demonstration that inflammation leads to an upregulation of eHsp90 on DRG nociceptors in a sex-dependent manner and that inhibition of eHsp90 reduces nociceptor activity, pain, and inflammation. Thus, eHsp90 represents a novel therapeutic axis for the development of gender-tailored treatments for inflammatory pain.

The Influence of Local Anesthesia Depth on Procedural Pain During Fluoroscopically Guided Lumbar Transforaminal Epidural Injections: A Randomized Clinical Trial.

OBJECTIVES: The aim of the study was to evaluate the influence of the depth of local anesthesia application on procedural pain during lumbar transforaminal epidural steroid injection. DESIGN: Sixty-eight patients were enrolled who were scheduled for single-level, unilateral fluoroscopically guided lumbar transforaminal epidural steroid injection. Patients were randomly allocated to receive either subcutaneous local anesthesia (group S) or deep local anesthesia (group D) for transforaminal epidural steroid injection. The data related to pain and technical performance during the procedure was compared. In addition, the incidence of injection site soreness was assessed 2 wks after transforaminal epidural steroid injection. RESULTS: Sixty-seven patients completed all assessments (group S, n = 33; group D, n = 34). There was no significant difference in procedural pain and discomfort level between the groups (P = 0.151, P = 0.183, respectively). Patients in group D showed lower behavioral pain scores (P = 0.017). There was no significant difference in the numbers of needle manipulations, fluoroscopy time, and radiation dose during the procedure between the groups. Two patients in group S and three in group D complained of injection site soreness after transforaminal epidural steroid injection for a few days, but there was no significant difference in its incidence (P = 0.667). CONCLUSIONS: Deep local anesthesia to reduce procedural pain during transforaminal epidural steroid injection seems to have no significant clinical benefit compared with conventional subcutaneous local anesthesia. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Reduce procedural pain by considering clinical factors of the patient during fluoroscopically guided lumbar transforaminal epidural injections.Upon completion of this article, the reader should be able to: (1) Understand the potential impact of procedural pain on the performance of transforaminal epidural steroid injections; (2) Distinguish cutaneous nociceptive afferents from nociceptive afferents in muscle; and (3) Explain the factors to reduce procedural pain during fluoroscopically guided lumbar transforaminal epidural injections. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Clinical effectiveness of the obturator externus muscle injection in chronic pelvic pain patients.

BACKGROUND: Because of its anatomical location and function, the obturator externus (OE) muscle can be a source of pain; however, this muscle is understudied as a possible target for therapeutic intervention in pain practice. In this retrospective observational study, we evaluated the clinical effectiveness of the OE muscle injection with a local anesthetic in chronic pelvic pain patients with suspected OE muscle problems. METHODS: Twenty-three patients with localized tenderness on the inferolateral side of the pubic tubercle accompanied by pain in the groin, anteromedial thigh, or hip were studied. After identifying the OE with contrast dye under fluoroscopic guidance, 5 to 8 mL of 0.3% lidocaine was injected. Pain scores were assessed before and after injection; patient satisfaction was also assessed. RESULTS: Mean pain score decreased by 44.7% (6.6 ± 1.8 to 3.5 ± 0.9, P < 0.001) 2 weeks after OE muscle injection as compared with pain score before injection. In addition, 82% of patients (19 of 23 patients) reported excellent or good satisfaction during 2 weeks after injection. No patients reported complications from OE muscle injection. CONCLUSIONS: Fluoroscopy-guided injection of the OE muscle with local anesthetic reduced pain scores and led to a high level of satisfaction at short-term follow-up in patients with suspected OE muscle problem. The results of this study suggest that OE muscle injection may be a valuable therapeutic option for a select group of chronic pelvic pain patients who present with localized tenderness in the OE muscle that is accompanied by groin, anteromedial thigh, or hip pain.