Changes in cardiovascular parameters in rats exposed to chronic widespread mechanical allodynia induced by hind limb cast immobilization.

To elucidate the relationship between chronic pain conditions with cast immobilization and autonomic function, we investigated the functional changes of the autonomic nervous system in conscious rats with chronic post-cast pain (CPCP) induced by a two-week cast immobilization of one hind limb. We telemetrically examined the time courses of systolic arterial blood pressure (SBP), heart rate (HR), and the middle-frequency (MF) component obtained from the power spectral analysis of SBP variability as a vasomotor sympathetic index. We also investigated the baroreflex sensitivity to phentolamine, an α-adrenoceptor antagonist, and the SBP and HR responses to a low ambient temperature (LT; 9.0 ± 0.2°C) exposure, a sympathetic stimulant. Rats exposed to cast immobilization exhibited mechanical allodynia lasting for at least 10 weeks after cast removal in the calf area (skin and muscle) of the bilateral hind limbs. Under resting conditions, the SBP, HR, and MF components were significantly increased during cast immobilization (all p < 0.001). Following cast removal, these parameters gradually decreased and within 1 week reached lower than baseline levels, lasting for over 10 weeks. Phentolamine administration (10 mg/kg, intraperitoneally) significantly decreased the SBP before and during cast immobilization (before, p < 0.001; during, p = 0.001) but did not lower the SBP after cast removal. The baroreflex gain after phentolamine administration, calculated as the HR increase divided by the SBP reduction, was significantly increased after cast removal (p = 0.002). The SBP increase on LT exposure was significantly greater after cast removal than that before cast immobilization, suggesting hypersensitivity to sympathetic neurotransmitters. These results revealed that, in the CPCP model, sympathetic activation was augmented during cast immobilization, which then decreased after cast removal and remained below normal levels with persisting pain behaviors. Additionally, the responsiveness of the autonomic nervous system was impaired in the CPCP model.

Associations between pain drawing and psychological characteristics of different body region pains.

BACKGROUND: Pain drawings have frequently been used for documentation of pain and a convenient diagnosis tool. Pain drawings were found to be associated with psychological states in chronic patients with low back pain. Few researchers have investigated pain drawings except in low back pain. The aim of this study was to investigate the pain, pain drawings, psychological characteristics, and pain interference in the head, neck-shoulder (NS), and low-back/lower-limb (LB-LL) regions among patients with chronic pain. METHODS: We included a total of 291 patients with new chronic pain (headache, 62; NS pain, 87; LB-LL pain, 142). The pain drawings and scores of 10-cm Visual Analogue Scale (VAS), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS), Short-Form McGill Pain Questionnaire (SF-MPQ), and Pain Disability Assessment Scale (PDAS) were extracted from medical records. A subset of 60 pain drawings was scored by senior and junior evaluators to assess inter-rater agreement. We investigated the correlation between pain drawings and VAS, HADS, PCS, SF-MPQ, and PDAS in each body region group at the initial visit. Moreover, almost all patients received nonsurgical treatment as a follow-up and were investigated using VAS after treatment. RESULTS: The reliability of pain drawings was substantial with an interevaluator reliability in headache, NS, and LB-LL pain. Nonorganic pain drawings were associated with psychological disturbances in NS and LB-LL pain, but not headache. Poor outcomes were associated with nonorganic drawings in LB-LL pain, but not in the case of headache or NS pain. CONCLUSIONS: Our results suggest that the characteristics of patients with nonorganic drawings differ according to body regions.

Activated spinal astrocytes are involved in the maintenance of chronic widespread mechanical hyperalgesia after cast immobilization.

BACKGROUND: In the present study, we examined spinal glial cell activation as a central nervous system mechanism of widespread mechanical hyperalgesia in rats that experienced chronic post-cast pain (CPCP) 2 weeks after cast immobilization. Activated spinal microglia and astrocytes were investigated immunohistologically in lumbar and coccygeal spinal cord segments 1 day, 5 weeks, and 13 weeks following cast removal. RESULTS: In the lumbar cord, astrocytes were activated after microglia. Astrocytes also were activated after microglia in the coccygeal cord, but with a delay that was longer than that observed in the lumbar cord. This activation pattern paralleled the observation that mechanical hyperalgesia occurred in the hindleg or the hindpaw before the tail. The activating transcription factor 3 (ATF3) immune response in dorsal root ganglia (DRG) on the last day of cast immobilization suggested that nerve damage might not occur in CPCP rats. The neural activation assessed by the phosphorylated extracellular signal-regulated kinase (pERK) immune response in DRG arose 1 day after cast removal. In addition, L-α-aminoadipate (L-α-AA), an inhibitor of astrocyte activation administered intrathecally 5 weeks after cast removal, inhibited mechanical hyperalgesia in several body parts including the lower leg skin and muscles bilaterally, hindpaws, and tail. CONCLUSIONS: These findings suggest that activation of lumbar cord astrocytes is an important factor in widespread mechanical hyperalgesia in CPCP.

The effects of exercise therapy for the improvement of jaw movement and psychological intervention to reduce parafunctional activities on chronic pain in the craniocervical region.

PURPOSE: Apparent organic abnormalities are sometimes not identified among patients suffering from chronic pain in the craniocervical region. In some cases, parafunctional activities (PAs) are recognized. PAs are nonfunctional oromandibular activities that include jaw clenching and bruxism, but are considered as factors that contribute to craniomandibular disorders (CMDs). It is now recognized that PAs and CMDs influence musculoskeletal conditions of the upper quarter. Exercise therapy (ET) to improve jaw movement and psychological intervention (PI) to reduce PAs are useful for PAs and CMDs. We hypothesized that ET and PI would be effective for craniocervical pain without organic abnormalities. METHODS: Thirty-nine subjects suffering from craniocervical chronic pain were allocated into 3 groups: The control group received only pharmacological treatment; the ET group received jaw movement exercise (JME); and the ET-PI group received JME and PI. Pain and jaw movement were evaluated using a numerical rating scale (NRS). RESULTS: After interventions, the NRS scores were significantly lower in the ET-PI group, compared with those in the other groups. Jaw movement improved 100% in the ET group, 92% in the ET-PI group, and 0% in the control group. CONCLUSION: A combination of jaw exercise and psychological intervention to reduce parafunctional activities is more effective than jaw exercise alone for the improvement of craniocervical pain without apparent organic abnormalities.

Treadmill running and static stretching improve long-lasting hyperalgesia, joint limitation, and muscle atrophy induced by cast immobilization in rats.

The effects of exercise on chronic pain induced by immobilization are incompletely understood. The purpose of this study was to investigate whether 30min of treadmill running (TR; active exercise) and 10min of static stretching (SS; passive exercise) of the immobilized hindlimb reduce widespread chronic pain, joint limitation, and hindlimb muscle atrophy induced by cast immobilization in rats. One hindlimb of Sprague Dawley (SD) rats was immobilized for 2 weeks with a cast, and remobilization was conducted for 7 weeks. MRI study showed that cast immobilization had induced inflammatory changes in the immobilized hindlimb, beginning as early as 2h after cast removal; these changes continued for 2-3 days. Mechanical hyperalgesia in the calf and hindpaw developed as early as 2h after cast removal and continued for 7 weeks. TR and SS were initiated 3 days after cast removal and were continued 3 times per week for 2 weeks. Both forms of exercise significantly inhibited mechanical hyperalgesia in the calf and hindpaw in immobilized rats. Range-of-motion limitations in the knee and ankle joints and calf muscle atrophy after cast removal were also decreased by both TR and SS. This study is the first to demonstrate the beneficial effect of TR and SS on widespread chronic pain, joint limitation, and muscle atrophy in a cast-immobilized rat model.

The effect of celiac plexus block on heart rate variability.

BACKGROUND: Celiac plexus block (CPB) can be used for treating intra-abdominal visceral pain syndromes. The celiac plexus is the largest plexus of the sympathetic nervous system. Several nerve blocks have a marked effect on autonomic nervous activity. Furthermore, stellate ganglion block changes cardiac autonomic nervous activity. Thus, CPB could influence the sympathetic activity of the cardiac plexus. The aim of the present study was to see whether CPB modulated heart rate variability (HRV) in patients with pancreatic cancer. METHODS: Twelve patients received neurolytic CPB using 14 ml absolute alcohol. Data recorded in a palm-sized electrocardiographic unit were analyzed for HRV. RESULTS: CPB using a neurolytic solution did not induce any significant changes in the low-frequency (LF)/high-frequency (HF) ratio of HRV (LF/HF, P = 0.4642). Furthermore, the procedure did not induce any significant changes in blood pressure (systolic, P = 0.5051; diastolic, P = 0.5180). CONCLUSION: CPB did not induce any significant changes in HRV or hemodynamics.

Frequency components of systolic blood pressure variability reflect vasomotor and cardiac sympathetic functions in conscious rats.

In this study, after confirming the suppression of autonomic nervous function by isoflurane anesthesia using autonomic antagonists, we pharmacologically investigated the involvement of vasomotor and cardiac sympathetic functions in systolic blood pressure variability (SBPV) frequency components in conscious rats at rest and during exposure to low-ambient temperature (LT-exposure, 9°C for 90 min). Under unanesthesia, phentolamine administration (α-adrenoceptor antagonist, 10 mg/kg) decreased the mid-frequency component (MF 0.33-0.73 Hz) and inversely increased the high-frequency component (HF 1.3-2.5 Hz). The increased HF was suppressed by subsequent treatment with atenolol (ß-adrenoceptor antagonist, 10 mg/kg), but not with atropine (muscarinic receptor antagonist, 10 mg/kg). Moreover, phentolamine administration after atenolol decreased MF, but did not increase HF. LT-exposure increased MF and HF; however, phentolamine pretreatment suppressed the increased MF during LT-exposure, and atenolol pretreatment dose-dependently decreased the increased HF. These results suggest that MF and HF of SBPV may reflect α-adrenoceptor-mediated vasomotor function and ß-adrenoceptor-mediated cardiac sympathetic function, respectively, in the conscious state.

Low rather than high dose lipopolysaccharide 'priming' of muscle provides an animal model of persistent elevated mechanical sensitivity for the study of chronic pain.

Experimental animal pain models involving peripheral nerve lesions have expanded the understanding of the pathological changes caused by nerve damage. However models for the pathogenesis of chronic pain patients lacking obvious nerve injuries have not been developed to the same extent. Guided by clinical observations, we focused on the initiating noxious event, the context when applying nociceptive stimulation targeting long-lasting pain elicited by muscle insult. The administration of a nociceptive agent (6% hypertonic saline: HS; 5-time repeated-injection: HS5) after pretreatment with an immuno-inflammatory agent (lipopolysaccharide: LPS, 2 µg/kg) into one gastrocnemius muscle produced markedly long-persisting biphasic sustained mechanical hypersensitivity on the plantar surface of both hindpaws. In the acute phase, the blockade of afferent inputs from the injected-site was effective in returning the contralateral enhanced-responses to baseline levels. In contrast, similar blockade during the chronic phase did not affect the contralateral enhanced-responses, indicating that the hypersensitivity in the two phases was probably induced by different mechanisms. However, increasing the dose of LPS (20 µg/kg) before applying HS5 eliminated the development of mechanical hypersensitivity in the chronic phase, while the hypersensitivity in the acute phase was significantly more severe than with low-dose LPS-pretreatment. In this model, the development of hypersensitivity could be modulated by manipulating LPS-doses prior to noxious stimulation. This novel chronic pain model based on a preceding 'priming' myalgic stimulus provides an intriguing means for studying the pathogenesis of chronic pain.

Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.

OBJECTIVES: To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS: The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS: Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter