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We validate the analgesic efficacy of tianeptine by different administration routes and timing in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of orally administered tianeptine and pretreatment with tianeptine (intrathecally or intraperitoneally) on mechanical allodynia were assessed. Oral and preemptive intrathecal administration of tianeptine significantly increased the paw withdrawal threshold but preemptive intraperitoneal administration did not. Nevertheless, intraperitoneal pretreatment of tianeptine potentiated the antiallodynic effects of subsequently administered tianeptine. These findings suggest that tianeptine may be effective for preventing and treating neuropathic pain and that it can be used more widely in clinical pain practice.

Neuropathic pain caused by nerve injury or compressive lesions is a debilitating condition lacking effective, long-term treatments. Our objective was to assess the effects of external focused ultrasound on sensory thresholds utilizing a common peroneal injury rat model. CPNI was induced by ligating the CPN of the left hind paw. Neuropathic phenotype was confirmed using the Von Frey Fibers (VFF) with a 50% mechanical detection threshold below 4.0. The Place Escape Avoidance Paradigm (PEAP) was employed as a behavioral correlate. External FUS treatment was applied to the left L4,5 DRG at 8 W for 3-min. There were two treatment groups; one received a single FUS treatment, while the other received two. Control groups consisted of one sham CPNI group that received FUS treatment and a CPNI group that received sham FUS treatment. Behavioral tests were conducted pre-CPNI surgery, 1-week post-surgery, and for 1-week post-FUS treatment(s). CPNI surgery resulted in lower VFF mechanical thresholds in the left hind paw compared to baseline (p 0.0001) and increased proportion of time spent on bright side compared to baseline values on PEAP (p = 0.0473), indicating neuropathic state. FUS treatment increased VFF thresholds after 24-hours (p 0.0001), 48-h (p = 0.0079), and 72-h (p = 0.0164). VFF returned to baseline values from day 4-7. Following a second FUS treatment on day 8, increased mechanical thresholds were similarly observed after 24-h (p = 0.0021), 48-h (p 0.0001), and 72-h (p = 0.0256). Control group analysis showed (1) CPNI rats experienced no change in mechanical thresholds following sham FUS treatment and (2) Sham CPNI rats receiving FUS did not experience significantly different mechanical thresholds compared to baseline and post-CPNI values. Post-FUS histological analysis demonstrated healthy ganglion cells without chromatolysis. Our results demonstrate changes in VFF and PEAP in rats who underwent CPNI. Single and multiple doses of external FUS increase mechanical thresholds without inducing histological damage. Based on our results, we have demonstrated the potential of FUS to serve as a non-pharmacological and non-ablative neuromodulatory approach for the treatment of allodynia and neuropathic pain.

The anterior cingulate cortex (ACC) has been extensively cited as a key area for processing pain affect. While local field potential (LFP) studies in other fields have yielded a great deal of information about neural oscillations, there is a poverty in the pain literature about the neural LFP profile related to pain, particularly in freely moving animals. In this study, we revealed the LFP profile in the ACC in freely moving rats during carrageenan inflammation. Mechanical allodynia was recorded before and after unilateral injection of carrageenan/saline in the left hindpaw. LFP activity in the ACC was recorded at baseline, after injection, and after injection with mechanical stimulation to the paw using a von Frey filament. This study uniquely reveals that carrageenan injection significantly recruited ACC LFP activity in delta, theta, and alpha bands (0-13Hz). Application of von Frey mechanical stimulation to the carrageenan-injected paw resulted in a significant increase in delta, theta, and alpha bands over and above what was recruited by carrageenan alone and further expanded the LFP range to additionally include beta activity (13-30Hz). Taken together, these data reveal significant changes in the lowest-frequency activities in the LFP range during painful inflammation, which merit attention. LFP is a powerful window to reveal wide-range, integrated synaptic processing by low-frequency cellular events during behavior. Information about LFP during pain broadens the scope of our understanding of pain mechanisms, our greatest resource for designing management approaches.

Antinociceptive effect of narcotic analgesics, fentanyl, oxycodone and methadone in inflammatory pain state was described in the von Frey filament test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After the i.pl. injection of CFA, mechanical allodynia (decrease of mechanical threshold) was observed in ipsilateral paw. The antinociceptive effect of fentanyl and oxycodone injected s.c. against mechanical allodynia in inflammatory pain state was reduced bilaterally at 1 day after CFA pretreatment. However, the antinociceptive effect of methadone injected s.c. against mechanical allodynia in inflammatory pain state was reduced unilaterally at 1 day after CFA pretreatment. Moreover, the reduction of the antinociceptive effect of methadone in ipsilateral paw on inflammatory pain state was smaller than those of fentanyl or oxycodone. In conclusion, the alternation of the antinociceptive effect of narcotic analgesics in inflammatory pain state is variable among the narcotic analgesics used.

The goal of this study was to investigate the effect of whole body vibration (WBV) on human tactile sensitivity, both the immediate effects and the recovery time in the case of altered sensitivity. Twenty adults (25.3±2.6 years, 10 males) participated in a 10-min WBV session, at a frequency of 42 Hz with 2 mm amplitude in a spiral mode. Sensitivity was measured before and four times after WBV exposure. Pressure sensation was determined using Von Frey monofilaments. Vibration perception thresholds for 30 and 200 Hz were measured using a custom built neurothesiometer. The sensation was measured in 5 anatomical regions of the right foot. Sensitivity of measured cutaneous perception was significantly reduced. Fast-adapting mechanoreceptors for 200 Hz and 30 Hz showed 5.2 and 3.8 times lower sensation values immediately after WBV, respectively. Pressure sensation was 2 times lower in comparison to the baseline condition. In general, tactile sensitivity recovery time was between 2 and 3 h. WBV influences the discharge of fast-adapting skin mechanoreceptors. By determining the recovery time, it might be possible to estimate how long the effects of WBV on tactile sensitivity last.

Several clinical studies have demonstrated a consistent relationship between changes in meteorological factors, particularly barometric pressure, and pain intensity in subjects with chronic pain. We have previously demonstrated that exposure to artificially low barometric pressure (LP) intensifies pain-related behaviors in rats with neuropathic pain. In the present study, guinea pigs with unilateral L5 spinal nerve ligation (SNL) were placed in a pressure-controlled chamber and subjected to LP of 10 or 27hPa below the ambient pressure. The SNL surgery led to increased hindpaw withdrawal frequencies to 34-, 59-, and 239-mN von Frey filaments (VFFs). When the SNL animals were subjected to both LP exposures consecutively, the hindpaw withdrawal frequencies further increased; the effect was most significant when the animals were exposed to LP 27hPa below ambient pressure. In contrast, no change was seen in a group of sham-operated control animals. These results indicate that fluctuations in LP within the range of natural weather patterns can potentiate neuropathic pain in guinea pigs.

We investigated the effect of the systemic infusion of brain derived neurotrophic factor (BDNF) on the behavioral response in a rat neuropathic pain model. One microgram per hour infusion of BDNF significantly attenuated mechanical hyperalgesia tested by the pin-prick test, however, 20 microg/h-BDNF infusion, on the contrary, enhanced the response. Neither 0.5 nor 10 microg/h-BDNF infusion influenced the mechanical hyperalgesia. Mechanical allodynia and thermal hyperalgesia, tested using a von Frey filament (23.0 mN) and the plantar test, were not influenced by BDNF treatment. These data suggest that systemic BDNF treatment can specifically alter high-threshold mechanosensitivity.