Muscle Activation During Peripheral Nerve Field Stimulation Occurs Due to Recruitment of Efferent Nerve Fibers, Not Direct Muscle Activation.

BACKGROUND: Peripheral nerve field stimulation (PNFS) is a potential treatment for chronic low-back pain. Pain relief using PNFS is dependent on activation of non-nociceptive Aß-fibers. However, PNFS may also activate muscles, causing twitches and discomfort. In this study, we developed a mathematical model, to investigate the activation of sensory and motor nerves, as well as direct muscle fiber activation. METHODS: The extracellular field was estimated using a finite element model based on the geometry of CT scanned lumbar vertebrae. The electrode was modeled as being implanted to a depth of 10-15 mm. Three implant directions were modeled; horizontally, vertically, and diagonally. Both single electrode and "between-lead" stimulation between contralateral electrodes were modeled. The extracellular field was combined with models of sensory Aß-nerves, motor neurons and muscle fibers to estimate their activation thresholds. RESULTS: The model showed that sensory Aß fibers could be activated with thresholds down to 0.563 V, and the lowest threshold for motor nerve activation was 7.19 V using between-lead stimulation with the cathode located closest to the nerves. All thresholds for direct muscle activation were above 500 V. CONCLUSIONS: The results suggest that direct muscle activation does not occur during PNFS, and concomitant motor and sensory nerve fiber activation are only likely to occur when using between-lead configuration. Thus, it may be relevant to investigate the location of the innervation zone of the low-back muscles prior to electrode implantation to avoid muscle activation.

Nerve Fiber Activation During Peripheral Nerve Field Stimulation: Importance of Electrode Orientation and Estimation of Area of Paresthesia.

INTRODUCTION AND AIM: Low back pain is one of the indications for using peripheral nerve field stimulation (PNFS). However, the effect of PNFS varies between patients; several stimulation parameters have not been investigated in depth, such as orientation of the nerve fiber in relation to the electrode. While placing the electrode parallel to the nerve fiber may give lower activation thresholds, anodal blocking may occur when the propagating action potential passes an anode. METHODS: A finite element model was used to simulate the extracellular potential during PNFS. This was combined with an active cable model of Aß and Aδ nerve fibers. It was investigated how the angle between the nerve fiber and electrode affected the nerve activation and whether anodal blocking could occur. Finally, the area of paresthesia was estimated and compared with any concomitant Aδ fiber activation. RESULTS: The lowest threshold was found when nerve and electrode were in parallel, and that anodal blocking did not appear to occur during PNFS. The activation of Aß fibers was within therapeutic range (<10V) of PNFS; however, within this range, Aδ fiber activation also may occur. The combined area of activated Aß fibers (paresthesia) was at least two times larger than Aδ fibers for similar stimulation intensities. CONCLUSION: No evidence of anodal blocking was observed in this PNFS model. The thresholds were lowest when the nerves and electrodes were parallel; thus, it may be relevant to investigate the overall position of the target nerve fibers prior to electrode placement.

Dynamic Pain Phenotypes are Associated with Spinal Cord Stimulation-Induced Reduction in Pain: A Repeated Measures Observational Pilot Study.

OBJECTIVE: Spinal cord stimulation (SCS) has become a widely used treatment option for a variety of pain conditions. Substantial variability exists in the degree of benefit obtained from SCS and patient selection is a topic of expanding interest and importance. However, few studies have examined the potential benefits of dynamic quantitative sensory testing (QST) to develop objective measures of SCS outcomes or as a predictive tool to help patient selection. Psychological characteristics have been shown to play an important role in shaping individual differences in the pain experience and may aid in predicting responses to SCS. Static laboratory pain-induction measures have also been examined in their capacity for predicting SCS outcomes. METHODS: The current study evaluated clinical, psychological and laboratory pain measures at baseline, during trial SCS lead placement, as well as 1 month and 3 months following permanent SCS implantation in chronic pain patients who received SCS treatment. Several QST measures were conducted, with specific focus on examination of dynamic models (central sensitization and conditioned pain modulation [CPM]) and their association with pain outcomes 3 months post SCS implantation. RESULTS: Results suggest few changes in QST over time. However, central sensitization and CPM at baseline were significantly associated with clinical pain at 3 months following SCS implantation, controlling for psycho/behavioral factors and pain at baseline. Specifically, enhanced central sensitization and reduced CPM were associated with less self-reported pain 3 months following SCS implantation. CONCLUSIONS: These findings suggest a potentially important role for dynamic pain assessment in individuals undergoing SCS, and hint at potential mechanisms through which SCS may impart its benefit.

Electrical stimulation of dorsal root entry zone attenuates wide-dynamic-range neuronal activity in rats.

OBJECTIVES: Recent clinical studies suggest that neurostimulation at the dorsal root entry zone (DREZ) may alleviate neuropathic pain. However, the mechanisms of action for this therapeutic effect are unclear. Here, we examined whether DREZ stimulation inhibits spinal wide-dynamic-range (WDR) neuronal activity in nerve-injured rats. MATERIALS AND METHODS: We conducted in vivo extracellular single-unit recordings of WDR neurons in rats after an L5 spinal nerve ligation (SNL) or sham surgery. We set bipolar electrical stimulation (50 Hz, 0.2 msec, 5 min) of the DREZ at the intensity that activated only Aα/ß-fibers by measuring the lowest current at which DREZ stimulation evoked a peak antidromic sciatic Aα/ß-compound action potential without inducing an Aδ/C-compound action potential (i.e., Ab1). RESULTS: The elevated spontaneous activity rate of WDR neurons in SNL rats (n = 25; data combined from post-SNL groups at days 14-16 [n = 15] and days 45-75 [n = 10]) was significantly decreased from the prestimulation level (p < 0.01) at 0-15 min and 30-45 min post-stimulation. In both sham-operated (n = 8) and nerve-injured rats, DREZ stimulation attenuated the C-component, but not the A-component, of the WDR neuronal response to graded intracutaneous electrical stimuli (0.1-10 mA, 2 msec) applied to the skin receptive field. Further, DREZ stimulation blocked windup (a form of brief neuronal sensitization) to repetitive noxious stimuli (0.5 Hz) at 0-15 min in all groups (p < 0.05). CONCLUSIONS: Attenuation of WDR neuronal activity may contribute to DREZ stimulation-induced analgesia. This finding supports the notion that DREZ may be a useful target for neuromodulatory control of pain.

Mathematical model of nerve fiber activation during low back peripheral nerve field stimulation: analysis of electrode implant depth.

OBJECTIVES: The lower back is the most common location of pain experienced by one-fifth of the European population reporting chronic pain. A peripheral nerve field stimulation system, which involves electrodes implanted subcutaneously in the painful area, has been shown to be efficacious for low back pain. Moreover, the predominant analgesic mechanism of action is thought to be via activation of peripheral Aß fibers. Unfortunately, electrical stimulation also might coactivate Aδ fibers, causing pain or unpleasantness itself. The aim of this study was to investigate at which implant depth Aß-fiber stimulation is maximized, and Aδ-fiber minimized, which in turn should lead to therapy optimization. MATERIALS AND METHODS: A finite element model was used to estimate the electrical potential generated by a bipolar single-lead electrode implanted in the subcutaneous adipose tissue at depths of 5 mm to 30 mm below the skin surface. The model includes low back tissue; the epidermis, dermis, adipose, and muscle layers, and nerve fibers, which were programmed to branch randomly in the model in a fiber type-specific manner. Likewise, activation thresholds were specific to Aß- and Aδ-fiber types and were estimated using a passive cable model. RESULTS: The stimulus-response functions showed that the skin area covered by Aß-fiber activation was larger than the area covered by Aδ-fiber activation at all depths and all intensities. The skin area covered by Aδ-fiber activation was largest when the electrode was modeled to have a superficial location (5 mm below the skin surface), while the skin area covered by Aß-fiber activation was largest at lower depths. CONCLUSIONS: The present mathematical model predicts an optimal implantation depth of 10 to 15 mm below the skin surface to achieve activation of the greatest area of Aß fibers and the smallest area of Aδ fibers. This finding may act as a guide for peripheral nerve field stimulation implant depth to treat low back pain.

Conventional and kilohertz-frequency spinal cord stimulation produces intensity- and frequency-dependent inhibition of mechanical hypersensitivity in a rat model of neuropathic pain.

BACKGROUND: Spinal cord stimulation (SCS) is a useful neuromodulatory technique for treatment of certain neuropathic pain conditions. However, the optimal stimulation parameters remain unclear. METHODS: In rats after L5 spinal nerve ligation, the authors compared the inhibitory effects on mechanical hypersensitivity from bipolar SCS of different intensities (20, 40, and 80% motor threshold) and frequencies (50, 1 kHz, and 10 kHz). The authors then compared the effects of 1 and 50 Hz dorsal column stimulation at high- and low-stimulus intensities on conduction properties of afferent Aα/ß-fibers and spinal wide-dynamic-range neuronal excitability. RESULTS: Three consecutive daily SCS at different frequencies progressively inhibited mechanical hypersensitivity in an intensity-dependent manner. At 80% motor threshold, the ipsilateral paw withdrawal threshold (% preinjury) increased significantly from pre-SCS measures, beginning with the first day of SCS at the frequencies of 1 kHz (50.2 ± 5.7% from 23.9 ± 2.6%, n = 19, mean ± SEM) and 10 kHz (50.8 ± 4.4% from 27.9 ± 2.3%, n = 17), whereas it was significantly increased beginning on the second day in the 50 Hz group (38.9 ± 4.6% from 23.8 ± 2.1%, n = 17). At high intensity, both 1 and 50 Hz dorsal column stimulation reduced Aα/ß-compound action potential size recorded at the sciatic nerve, but only 1 kHz stimulation was partially effective at the lower intensity. The number of actions potentials in C-fiber component of wide-dynamic-range neuronal response to windup-inducing stimulation was significantly decreased after 50 Hz (147.4 ± 23.6 from 228.1 ± 39.0, n = 13), but not 1 kHz (n = 15), dorsal column stimulation. CONCLUSIONS: Kilohertz SCS attenuated mechanical hypersensitivity in a time course and amplitude that differed from conventional 50 Hz SCS, and may involve different peripheral and spinal segmental mechanisms.

Differential effects of subcutaneous electrical stimulation (SQS) and transcutaneous electrical nerve stimulation (TENS) in rodent models of chronic neuropathic or inflammatory pain.

OBJECTIVES: Electrical stimulation has been used for many years for the treatment of pain. Present-day research demonstrates that stimulation targets and parameters impact the induction of specific pain-modulating mechanisms. New targets are increasingly being investigated clinically, but the scientific rationale for a particular target is often not well established. This present study compares the behavioral effects of targeting peripheral axons by electrode placement in the subcutaneous space vs. electrode placement on the surface of the skin in a rodent model. MATERIALS AND METHODS: Rodent models of inflammatory and neuropathic pain were used to investigate subcutaneous electrical stimulation (SQS) vs. transcutaneous electrical nerve stimulation (TENS). Electrical parameters and relative location of the leads were held constant under each condition. RESULTS: SQS had cumulative antihypersensitivity effects in both inflammatory and neuropathic pain rodent models, with significant inhibition of mechanical hypersensitivity observed on days 3-4 of treatment. In contrast, reduction of thermal hyperalgesia in the inflammatory model was observed during the first four days of treatment with SQS, and reduction of cold allodynia in the neuropathic pain model was seen only on the first day with SQS. TENS was effective in the inflammation model, and in agreement with previous studies, tolerance developed to the antihypersensitivity effects of TENS. With the exception of a reversal of cold hypersensitivity on day 1 of testing, TENS did not reveal significant analgesic effects in the neuropathic pain rodent model. CONCLUSIONS: The results presented show that TENS and SQS have different effects that could point to unique biologic mechanisms underlying the analgesic effect of each therapy. Furthermore, this study is the first to demonstrate in an animal model that SQS attenuates neuropathic and inflammatory-induced pain behaviors.

Reliability of Wearable Sensors for Assessing Gait and Chair Stand Function at Home in People With Knee Osteoarthritis.

OBJECTIVE: To assess the reliability of wearable sensors for at-home assessment of walking and chair stand activities in people with knee osteoarthritis (OA). METHODS: Baseline data from participants with knee OA (n = 20) enrolled in a clinical trial of an exercise intervention were used. Participants completed an in-person laboratory visit and a video conference-enabled at-home visit. In both visits, participants performed walking and chair stand tasks while fitted with 3 inertial sensors. During the at-home visit, participants self-donned the sensors and completed 2 sets of acquisitions separated by a 15-minute break, when they removed and redonned the sensors. Participants completed a survey on their experience with the at-home visit. During the laboratory visit, researchers placed the sensors on the participants. Spatiotemporal metrics of walking gait and chair stand duration were extracted from the sensor data. We used intraclass correlation coefficients (ICCs) and the Bland-Altman plot for statistical analyses. RESULTS: For test-retest reliability during the at-home visit, all ICCs were good to excellent (0.85-0.95). For agreement between at-home and laboratory visits, ICCs were moderate to good (0.59-0.87). Systematic differences were noted between at-home and laboratory data due to faster task speed during the laboratory visits. Participants reported a favorable experience during the at-home visit. CONCLUSION: Our method of estimating spatiotemporal gait measures and chair stand duration function remotely was reliable, feasible, and acceptable in people with knee OA. Wearable sensors could be used to remotely assess walking and chair stand in participant's natural environments in future studies.

Spinal cord stimulation-induced analgesia: electrical stimulation of dorsal column and dorsal roots attenuates dorsal horn neuronal excitability in neuropathic rats.

BACKGROUND: The sites of action and cellular mechanisms by which spinal cord stimulation reduces neuropathic pain remain unclear. METHODS: We examined the effect of bipolar electrical-conditioning stimulation (50 Hz, 0.2 ms, 5 min) of the dorsal column and lumbar dorsal roots on the response properties of spinal wide dynamic range (WDR) neurons in rats after L5 spinal nerve injury. The conditioning stimulation intensity was set at the lowest current that evoked a peak antidromic sciatic Aα/ß-compound action potential without inducing an Aδ- or C-compound action potential. RESULTS: Within 15 min of the dorsal column or root conditioning stimulation, the spontaneous activity rate of WDR neurons was significantly reduced in nerve-injured rats. Conditioning stimulation also significantly attenuated WDR neuronal responses to mechanical stimuli in nerve-injured rats and inhibited the C-component of the neuronal response to graded intracutaneous electrical stimuli applied to the receptive field in nerve-injured and sham-operated rats. It is noteworthy that dorsal column stimulation blocked windup of WDR neuronal response to repetitive intracutaneous electrical stimulation (0.5 Hz) in nerve-injured and sham-operated rats, whereas dorsal root stimulation inhibited windup only in sham-operated rats. Therefore, stimulation of putative spinal substrates at A-fiber intensities with parameters similar to those used by patients with spinal cord stimulators attenuated established WDR neuronal hyperexcitability in the neuropathic condition and counteracted activity-dependent increase in neuronal excitability (i.e., windup). CONCLUSIONS: These results suggest a potential cellular mechanism underlying spinal cord stimulation-induced pain relief. This in vivo model allows the neurophysiologic basis for spinal cord stimulation-induced analgesia to be studied.

Cannabinoids affect dendritic cell (DC) potassium channel function and modulate DC T cell stimulatory capacity.

Cannabinoids affect diverse biological processes, including functions of the immune system. With respect to the immune system, anti-inflammatory and immunosuppressive effects of cannabinoids have been reported. Cannabinoids stimulate G protein-coupled cannabinoid receptors CB1 and CB2. These receptors are found primarily on neurons. However, they are also found on dendritic cells (DC), which are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoids. We report in this study that cannabinoids reduced the DC surface expression of MHC class II molecules as well as their capacity to stimulate T cells. In the nervous system, CB1 receptor signaling modulates K(+) and Ca(2+) channels. Interestingly, cannabinoid-treated DC also showed altered voltage-gated potassium (K(V)) channel function. We speculate that attenuation of K(V) channel function via CB1 receptor signaling in DC may represent one mechanism by which cannabinoids alter DC function.

mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson's disease.

Accurately monitoring motor and non-motor symptoms as well as complications in people with Parkinson's disease (PD) is a major challenge, both during clinical management and when conducting clinical trials investigating new treatments. A variety of strategies have been relied upon including questionnaires, motor diaries, and the serial administration of structured clinical exams like part III of the MDS-UPDRS. To evaluate the potential use of mobile and wearable technologies in clinical trials of new pharmacotherapies targeting PD symptoms, we carried out a project (project BlueSky) encompassing four clinical studies, in which 60 healthy volunteers (aged 23-69; 33 females) and 95 people with PD (aged 42-80; 37 females; years since diagnosis 1-24 years; Hoehn and Yahr 1-3) participated and were monitored in either a laboratory environment, a simulated apartment, or at home and in the community. In this paper, we investigated (i) the utility and reliability of self-reports for describing motor fluctuations; (ii) the agreement between participants and clinical raters on the presence of motor complications; (iii) the ability of video raters to accurately assess motor symptoms, and (iv) the dynamics of tremor, dyskinesia, and bradykinesia as they evolve over the medication cycle. Future papers will explore methods for estimating symptom severity based on sensor data. We found that 38% of participants who were asked to complete an electronic motor diary at home missed ~25% of total possible entries and otherwise made entries with an average delay of >4 h. During clinical evaluations by PD specialists, self-reports of dyskinesia were marked by ~35% false negatives and 15% false positives. Compared with live evaluation, the video evaluation of part III of the MDS-UPDRS significantly underestimated the subtle features of tremor and extremity bradykinesia, suggesting that these aspects of the disease may be underappreciated during remote assessments. On the other hand, live and video raters agreed on aspects of postural instability and gait. Our results highlight the significant opportunity for objective, high-resolution, continuous monitoring afforded by wearable technology to improve upon the monitoring of PD symptoms.

Tumor-induced mechanical hyperalgesia involves CGRP receptors and altered innervation and vascularization of DsRed2 fluorescent hindpaw tumors.

Functional and anatomical relationships among primary afferent fibers, blood vessels, and cancers are poorly understood. However, recent evidence suggests that physical and biochemical interactions between these peripheral components are important to both tumor biology and cancer-associated pain. To determine the role of these peripheral components in a mouse model of cancer pain, we quantified the change in nerve and blood vessel density within a fibrosarcoma tumor mass using stereological analysis of serial confocal optical sections of immunostained hind paw. To this end we introduced the Discoma coral-derived red fluorescent protein (DsRed2) into the NCTC 2472 fibrosarcoma line using the Sleeping Beauty transposon methodology, thus providing a unique opportunity to visualize tumor-nerve-vessel associations in context with behavioral assessment of tumor-associated hyperalgesia. Tumors from hyperalgesic mice are more densely innervated with calcitonin gene related peptide (CGRP)-immunoreactive nerve fibers and less densely vascularized than tumors from non-hyperalgesic mice. As hyperalgesia increased from Day 5 to 12 post-implantation, the density of protein gene product 9.5 (PGP9.5)-immunoreactive nerves and CD31-immunoreactive blood vessels in tumors decreased, whereas CGRP-immunoreactive nerve density remained unchanged. Importantly, intra-tumor injection of a CGRP1 receptor antagonist (CGRP 8-37) partially blocked the tumor-associated mechanical hyperalgesia, indicating that local production of CGRP may contribute to tumor-induced nociception through a receptor-mediated process. The results describe for the first time the interaction among sensory nerves, blood vessels and tumor cells in otherwise healthy tissue, and our assessment supports the hypothesis that direct tumor cell-axon communication may underlie, at least in part, the occurrence of cancer pain.

A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain.

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.

Tumor implantation in mouse humerus evokes movement-related hyperalgesia exceeding that evoked by intramuscular carrageenan.

In this paper we compare two innovative models of movement-related pain: tumor-induced nociception following implantation of fibrosarcoma cells into bone and muscle inflammation-induced nociception following injection of the irritant carrageenan into muscle. Importantly, using the grip force test, an assay of movement-related hyperalgesia, both non-malignant and malignant pain are examined in parallel. Movement-related hyperalgesia, known clinically as a specific type of 'breakthrough pain', is a common feature of bone cancer and is thought to be a predictor of poor response to conventional analgesic pharmacotherapy (Bruera et al., 1995, J. Pain Symptom. Manage. 10 (1995) 348; Mercadaute et al., 1992, Pain 50 (1992) 151; Pain 81 (1999) 129). Implantation of NCTC 2472 sarcoma cells in both humeri or injection of carrageenan (4%) in both triceps of C3H/He mice produced apparent forelimb hyperalgesia that was not associated with mechanical hyperalgesia in the forepaw, whereas carrageenan at 6 and 8% did evoke significant cutaneous hyperalgesia of the forepaw as well. Control groups receiving implants of vehicle or no treatment at all did not manifest this forelimb hyperalgesia. B6C3/F1 mice implanted with non-lysis-inducing G3.26 melanoma cells or vehicle did not manifest significant hyperalgesia when compared to B6C3/F1 mice receiving fibrosarcoma cells, indicating a dependence on bone involvement for induction of hyperalgesia in this model. Histological examination at days 3, 7, and 10 post-implantation showed a clear correlation of tumor growth-induced bone destruction with behavioral hyperalgesia. Morphine was more potent in decreasing the maximal hyperalgesia induced by carrageenan than that induced by tumor implantation. Acutely administered morphine (3-100mg/kg, i.p.) attenuated peak hyperalgesia of carrageenan-injected mice (ED(50) 6.9 mg/kg) and tumor-bearing mice (ED(50) 23.9 mg/kg) in a dose-related manner with a difference in potency of 3.5. Tumor-implanted mice with a level of hyperalgesia comparable to that induced by carrageenan required almost three times more morphine (ED(50) 18.5mg/kg) for equivalent attenuation of forelimb hyperalgesia. These animal models of movement-related hyperalgesia may aid in discerning the peripheral and central mechanisms underlying pain that accompanies bone metastases and distinguishing it from the pain associated with muscular inflammation. Importantly, they may also aid in predicting differences in analgesic efficacy in different types of musculoskeletal pain.

Analgesic effects of a soy-containing diet in three murine bone cancer pain models.

UNLABELLED: Bone is a common metastatic site for prostate and breast cancer, and bone cancer is usually associated with severe pain. Traditional treatments for cancer pain can sometimes be ineffective or associated with side effects. Thus an increasing number of patients seek alternative therapies. In this study we investigated the analgesic effects of a soy diet on 3 experimental models of bone cancer pain. Mice were fed a diet in which the protein source was either soy or casein. After 1 week on the diet, sarcoma cells (NCTC 2472) were injected into the medullary cavity of the humeri, femur, or calcaneus. Experimenters blinded to diet of the animal assessed the pain behavior in these animals, forelimb grip force in the humerus model and paw withdrawal frequency to mechanical stimuli in the calcaneus and femur models. The effect of morphine on cancer-induced pain behavior was investigated in calcaneus and femur models. In addition, in the femur model, the effects of soy on tumor size and bone destruction were studied. The soy diet reduced secondary mechanical hyperalgesia in the femur model but had no effect on primary mechanical hyperalgesia in the calcaneus model or on movement-related hyperalgesia in the humerus model. No dietary impact was discerned in measurements of tumor size, bone destruction, and body weight in the femur model, suggesting that the soy diet had no effect on cancer growth. Morphine dose-dependently reduced hyperalgesia with no diet-based difference. These results suggest that a soy diet might provide analgesia in certain forms of hyperalgesia associated with bone cancer. PERSPECTIVE: The study raises the possibility of dietary supplements influencing aspects of cancer pain. Further research will help determine if use of nutritional supplements, such as soy proteins, can reduce opioid analgesic use in chronic pain states and help minimize the side effects associated with long term use of opioids.

Effects of acute intrathecal baclofen in an animal model of TBI-induced spasticity, cognitive, and balance disabilities.

Spasticity is a major health problem for patients with traumatic brain injury (TBI). In addition to spasticity, TBI patients exhibit enduring cognitive, balance, and other motor impairments. Although the use of antispastic medications, particularly ITB, can decrease the severity of TBI-induced spasticity, current guidelines preclude the use of ITB during the first year after TBI. Therefore, the present study was performed to quantitate disability in an animal model of closed-head TBI (cTBI; Mararou's model) after ITB treatment. After cTBI, significant deficits in spasticity and gait, cognitive, balance, and anxiety-like behaviors were detected. ITB (Lioresal(®)) or saline was administered using Alzet pumps (0.8 µg/hour for 4 weeks). Spasticity measures using velocity-dependent ankle torque and ankle extensor muscle electromyography recordings, footprints (gait), balance performance tests, serial learning, and anxiety-like behaviors were performed at multiple post-treatment and -withdrawal of ITB time points. Our data indicated that 1 month of ITB treatment initiated at post-TBI week 1 blocked the early onset of spasticity and significantly attenuated late-onset spasticity and anxiety-like behavior with no significant adverse effects on cognitive and balance performance. This improved spasticity outcome was accompanied by marked up-regulation of gamma-aminobutyric acid (GABA)/GABAb, norepinephrine, and brain-derived neurotrophic factor expression in spinal cord tissue. Early intervention with ITB treatment was safe, feasible, and effective in this cTBI animal model. Collectively, these data provide a strong molecular footprint of enhanced expression of reflex regulation by presynaptic inhibition. The possibility that acute ITB treatment may decrease maladaptive segmental and descending plasticity is discussed. The data provided by the present animal model initiates a pre-clinical platform for safety, feasibility, and efficacy of early ITB intervention after TBI.

Electrical stimulation at distinct peripheral sites in spinal nerve injured rats leads to different afferent activation profiles.

The neurophysiological basis by which neuromodulatory techniques lead to relief of neuropathic pain remains unclear. We investigated whether electrical stimulation at different peripheral sites induces unique profiles of A-fiber afferent activation in nerve-injured rats. At 4-6weeks after subjecting rats to L5 spinal nerve injury (SNL) or sham operation, we recorded the orthodromic compound action potential (AP) at the ipsilateral L4 dorsal root in response to (1) transcutaneous electrical nerve stimulation (TENS, a patch electrode placed on the dorsum of the foot), (2) subcutaneous electrical stimulation (SQS, electrode inserted subcutaneously along the dorsum of the foot), (3) peroneal nerve stimulation (PNS, electrode placed longitudinally abutting the nerve), and (4) sciatic nerve stimulation (SNS). The area under the Aα/ß compound AP was measured as a function of the bipolar, constant-current stimulus intensity (0.02-6.0 mA, 0.2 ms). In both nerve-injured and sham-operated groups, the stimulus-response (S-R) functions of the Aα/ß compound APs differed substantially with the stimulation site; SNS having the lowest threshold and largest compound AP waveform, followed by PNS, SQS, and TENS. The S-R function to PNS was shifted to the right in the SNL group, compared to that in the sham-operated group. The Aα/ß-threshold to PNS was higher in the SNL group than in the sham-operated group. The S-R functions and Aα/ß-thresholds to TENS and SQS were comparable between the two groups. Electrical stimulation of different peripheral targets induced distinctive profiles of A-fiber afferent activation, suggesting that the neuronal substrates for the various forms of peripheral neuromodulatory therapies may differ.