Complex Regional Pain Syndrome Type I: Evidence for the CB1 and CB2 Receptors Immunocontent and Beneficial Effect of Local Administration of Cannabidiol in Mice.

Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.

Peripheral Activation of Formyl Peptide Receptor 2/ALX by Electroacupuncture Alleviates Inflammatory Pain by Increasing Interleukin-10 Levels and Catalase Activity in Mice.

In the context of the electroacupuncture (EA) neurobiological mechanisms, we have previously demonstrated the involvement of formyl peptide receptor 2 (FPR2/ALX) in the antihyperalgesic effect of EA. The present study investigated the involvement of peripheral FPR2/ALX in the antihyperalgesic effect of EA on inflammatory cytokines levels, oxidative stress markers and antioxidant enzymes in an animal model of persistent inflammatory pain. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2/10 Hz, ST36-SP6, 20 minutes) for 4 consecutive days. From the first to the fourth day after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or saline before EA. Levels of inflammatory cytokines (TNF, IL-6, IL-4 and IL-10), antioxidant enzymes (catalase and superoxide dismutase), oxidative stress markers (TBARS, protein carbonyl, nitrite/nitrate ratio), and myeloperoxidase activity were measured in paw tissue samples. As previously demonstrated, i.pl. injection of the FPR2/ALX antagonist prevented the antihyperalgesic effect induced by EA. Furthermore, animals treated with EA showed higher levels of IL-10 and catalase activity in the inflamed paw, and these effects were prevented by the antagonist WRW4. EA did not change levels of TNF and IL-6, SOD and MPO activity, and oxidative stress markers. Our work demonstrates that the antihyperalgesic effect of EA on CFA-induced inflammatory pain could be partially associated with higher IL-10 levels and catalase activity, and that these effects may be dependent, at least in part, on the activation of peripheral FPR2/ALX.

Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels.

The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.

Electrical Stimulation of the Auricular Branch Vagus Nerve Using Random and Alternating Frequencies Triggers a Rapid Onset and Pronounced Antihyperalgesia via Peripheral Annexin A1-Formyl Peptide Receptor 2/ALX Pathway in a Mouse Model of Persistent Inflammatory Pain.

This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) by comparing the effects of alternating and random frequencies in an animal model of persistent inflammatory hyperalgesia. The model was induced by Freund's complete adjuvant (CFA) intraplantar (i.pl.) injection. Mice were treated with different protocols of time (10, 20, or 30 min), ear laterality (right, left or both), and frequency (alternating or random). Mechanical hyperalgesia was evaluated, and some groups received i.pl. WRW4 (FPR2/ALX antagonist) to determine the involvement. Edema, paw surface temperature, and spontaneous locomotor activity were evaluated. Interleukin-1ß, IL-6, IL-10, and IL4 levels were verified by enzyme-linked immunosorbent assay. AnxA1, FPR2/ALX, neutrophil, M1 and M2 phenotype macrophage, and apoptotic cells markers were identified using western blotting. The antihyperalgesic effect pVNS with alternating and random frequency effect is depending on the type of frequency, time, and ear treated. The pVNS random frequency in the left ear for 10 min had a longer lasting antihyperalgesic effect, superior to classical stimulation using alternating frequency and the FPR2/ALX receptor was involved in this effect. There was a reduction in the levels of pro-inflammatory cytokines and an increase in the immunocontent of AnxA1 and CD86 in mice paw. pVNS with a random frequency in the left ear for 10 min showed to be optimal for inducing an antihyperalgesic effect. Thus, the random frequency was more effective than the alternating frequency. Therefore, pVNS may be an important adjunctive treatment for persistent inflammatory pain.

In vivo measurement of intradiscal pressure changes related to thrust and non-thrust spinal manipulation in an animal model: a pilot study.

BACKGROUND: The intervertebral disc is a known back pain generator and is frequently the focus of spinal manipulative therapy evaluation and treatment. The majority of our current knowledge regarding intradiscal pressure (IDP) changes related to spinal manual therapy involves cadaveric studies with their inherent limitations. Additional in vivo animal models are needed to investigate intervertebral disc physiological and molecular mechanisms related to spinal manipulation and spinal mobilization treatment for low back disorders. METHODS: Miniature pressure catheters (Millar SPR-1000) were inserted into either the L4-L5 or L5-L6 intervertebral disc of 3 deeply anesthetized adult cats (Oct 2012-May 2013). Changes in IDP were recorded during delivery of instrument-assisted spinal manipulation (Activator V® and Pulstar®) and motorized spinal flexion with/without manual spinous process contact. RESULTS: Motorized flexion of 30° without spinous contact decreased IDP of the L4-L5 disc by ~ 2.9 kPa, while physical contact of the L4 spinous process decreased IDP an additional ~ 1.4 kPa. Motorized flexion of 25° with L5 physical contact in a separate animal decreased IDP of the L5-L6 disc by ~ 1.0 kPa. Pulstar® impulses (setting 1-3) increased IDP of L4-L5 and L5-L6 intervertebral discs by ~ 2.5 to 3.0 kPa. Activator V® (setting 1-4) impulses increased L4-L5 IDP to a similar degree. Net changes in IDP amplitudes remained fairly consistent across settings on both devices regardless of device setting suggesting that viscoelastic properties of in vivo spinal tissues greatly dampen superficially applied manipulative forces prior to reaching deep back structures such as the intervertebral disc. CONCLUSIONS: This study marks the first time that feline in vivo changes in IDP have been reported using clinically available instrument-assisted spinal manipulation devices and/or spinal mobilization procedures. The results of this pilot study indicate that a feline model can be used to investigate IDP changes related to spinal manual therapy mechanisms as well as the diminution of these spinal manipulative forces due to viscoelastic properties of the surrounding spinal tissues. Additional investigation of IDP changes is warranted in this and/or other in vivo animal models to provide better insights into the physiological effects and mechanisms of spinal manual therapy at the intervertebral disc level.

Preventive Supplementation of Omega-3 Reduces Pain and Pro-inflammatory Cytokines in a Mouse Model of Complex Regional Pain Syndrome Type I.

Complex regional pain syndrome type I (CRPS-I) is a condition that responds poorly to treatments. The role of omega-3 fatty acids in the treatment of inflammatory disorders is well described in the literature; however, few studies have evaluated its therapeutic benefits in different types of pain. We evaluated the potential antihyperalgesic and anti-inflammatory effects of preventive omega-3 supplementation in an animal model of CRPS-I. In experiment 1, Swiss female mice were supplemented for 30 days with omega-3 before the induction of the CRPS-I model and 14 days after. Mechanical hyperalgesia was evaluated at baseline and from the 4th to the 14th day after CPRS-I induction along with open field locomotor activity after 30 days of supplementation. In experiment 2, Swiss female mice were supplemented for 30 days with omega-3 and then subjected to the CRPS-I model. Twenty-four hours later the animals were euthanized, and tissue samples of the spinal cord and right posterior paw muscle were taken to measure pro-inflammatory cytokine TNF and IL-1ß concentrations. Omega-3 supplementation produced antihyperalgesic and anti-inflammatory effects, as well as reducing pro-inflammatory cytokine concentrations, without altering the animals' locomotion. No open field locomotor changes were found. The 30-day supplementation at the tested dose was effective in the CRPS-I model.

Effects of low-intensity training on the brain and muscle in the congenital muscular dystrophy 1D model.

INTRODUCTION: Congenital Muscular Dystrophy type 1D (MDC1D) is characterized by a hypoglycosylation of α-dystroglycan protein (α-DG), and this may be strongly implicated in increased skeletal muscle tissue degeneration and abnormal brain development, leading to cognitive impairment. However, the pathophysiology of brain involvement is still unclear. Low-intensity exercise training (LIET) is known to contribute to decreased muscle degeneration in animal models of other forms of progressive muscular dystrophies. AIM: The objective of this study was to analyze the effects of LIET on cognitive involvement and oxidative stress in brain tissue and gastrocnemius muscle. METHODS: Male homozygous (Largemyd-/-), heterozygous (Largemyd+/-), and wild-type mice were used. To complete 28 days of life, they were subjected to a low-intensity exercise training (LIET) for 8 weeks. After the last day of training, 24 h were expected when the animals were submitted to inhibitory avoidance and open-field test. The striatum, prefrontal cortex, hippocampus, cortex, and gastrocnemius were collected for evaluation of protein carbonylation, lipid peroxidation, and catalase and superoxide dismutase activity. RESULTS: LIET was observed to reverse the alteration in aversive and habituation memory. Increased protein carbonylation in the striatum, prefrontal cortex, and hippocampus and lipid peroxidation in the prefrontal cortex and hippocampus were also reversed by LIET. In the evaluation of the antioxidant activity, LIET increased catalase activity in the hippocampus and cortex. In the gastrocnemius, LIET decreased the protein carbonylation and lipid peroxidation and increased catalase and superoxide dismutase activity. CONCLUSION: In conclusion, it can be inferred that LIET for 8 weeks was able to reverse the cognitive damage and oxidative stress in brain tissue and gastrocnemius muscle in MDC1D animals.

Potential Nociceptive Role of the Thoracolumbar Fascia: A Scope Review Involving In Vivo and Ex Vivo Studies.

Nociceptive innervation of the thoracolumbar fascia (TLF) has been investigated over the past few decades; however, these studies have not been compiled or collectively appraised. The purpose of this scoping review was to assess current knowledge regarding nociceptive innervation of the TLF to better inform future mechanistic and clinical TLF research targeting lower back pain (LBP) treatment. PubMed, ScienceDirect, Cochrane, and Embase databases were searched in January 2021 using relevant descriptors encompassing fascia and pain. Eligible studies satisfied the following: (a) published in English; (b) preclinical and clinical (in vivo and ex vivo) studies; (c) original data; (d) included quantification of at least one TLF nociceptive component. Two-phase screening procedures were conducted by a pair of independent reviewers, after which data were extracted and summarized from eligible studies. The search resulted in 257 articles of which 10 met the inclusion criteria. Studies showed histological evidence of nociceptive nerve fibers terminating in lower back fascia, suggesting a TLF contribution to LBP. Noxious chemical injection or electrical stimulation into fascia resulted in longer pain duration and higher pain intensities than injections into subcutaneous tissue or muscle. Pre-clinical and clinical research provides histological and functional evidence of nociceptive innervation of TLF. Additional knowledge of fascial neurological components could impact LBP treatment.

The role of the vagus nerve in fibromyalgia syndrome.

Fibromyalgia (FM) syndrome is a common illness characterized by chronic widespread pain, sleep problems, fatigue, and cognitive difficulties. Dysfunctional neurotransmitter systems that influence the body's endogenous stress response systems are thought to underlie many of the major FM-related symptoms. A model of FM pathogenesis suggests biological and psychosocial variables interact to influence the genetic predisposition, but the precise mechanisms remain unclear. The Polyvagal Theory provides a theoretical framework from which to investigate potential biological mechanisms. The vagus nerve (VN) has anti-inflammatory properties via its afferent and efferent fibers. A low vagal tone (as assessed by low heart rate variability), has been observed in painful and inflammatory diseases, including FM, while the ventral branch of the VN is linked to emotional expression and social engagement. These anti-inflammatory and psychological (limbic system) properties of the VN may possess therapeutic potential in treating FM. This review paper summarizes the scientific literature regarding the potential role of the VN in transducing and/or therapeutically managing FM signs and symptoms.

Influence of Intervertebral Fixation and Segmental Thrust Level on Immediate Post-Spinal Manipulation Trunk Muscle Spindle Response in an Animal Model.

OBJECTIVE: To characterize the effect of unilateral (single and two-level) lumbar facet/zygapophysial joint fixation on paraspinal muscle spindle activity immediately following L4 or L6 high velocity low amplitude spinal manipulation (HVLA-SM) delivered at various thrust durations. METHODS: Secondary analysis of immediate (≤2 s) post-HVLA-SM trunk muscle spindle response from two studies involving anesthetized adult cats (n = 39; 2.3-6.0 kg) with either a unilateral single (L5/6) or two-level (L5/6 and L6/7) facet joint fixation. All facet fixations were contralateral to L6 dorsal root recordings. HVLA-SM was delivered to the spinous process in a posterior-to-anterior direction using a feedback motor with a peak thrust magnitude of 55% of average cat body weight and thrust durations of 75, 100, 150, and 250 ms. Time to 1st action potential and spindle activity during 1 and 2 s post-HVLA-SM comparisons were made between facet joint fixation conditions and HVLA-SM segmental thrust levels. RESULTS: Neither two-level facet joint fixation, nor HVLA-SM segmental level significantly altered immediate post-HVLA-SM spindle discharge at tested thrust durations (FDR > 0.05). CONCLUSIONS: Two-level facet joint fixation failed to alter immediate (≤2 s) post-HVLA-SM spindle discharge when compared to single-level facet joint fixation at any thrust duration. Segmental thrust level did not alter immediate post-HVLA-SM spindle response in two-level facet joint fixation preparations.

The Neurophysiological Impact of Experimentally-Induced Pain on Direct Muscle Spindle Afferent Response: A Scoping Review.

Background: Musculoskeletal pain disorders are among the leading causes of years lived with disability worldwide representing a significant burden to society. Studies investigating a "nociceptive-fusimotor" relationship using experimentally-induced pain/noxious stimuli and muscle spindle afferent (MSA) response have been published over several decades. The purpose of this scoping review was to systematically identify and summarize research findings related to the impact of experimentally-induced pain or noxious stimulation on direct MSA discharge/response. Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane and Embase were searched from database inception to August 2020. Eligible studies were: (a) published in English; (b) clinical or pre-clinical studies; (c) original data studies; (d) included the investigation of MSA response to experimentally-induced pain or noxious stimulation; (e) included quantification of at least one direct physiological measure associated with MSA activity/response. Two-phase screening procedures were conducted by a pair of independent reviewers and data extracted from eligible studies. Results: The literature search resulted in 195 articles of which 23 met inclusion criteria. Six studies (26%) were classified as clinical and 17 (74%) as pre-clinical. Two clinical studies investigated the effects of sacral dermatome pin-pricking on MSA response, while the remaining 4 studies investigated the effects of tonic muscle and/or skin pain induced by injection/infusion of hypertonic saline into the tibialis anterior muscle or subdermal tissues. In pre-clinical studies, muscle pain was induced by injection of noxious substances or the surgical removal of the meniscus at the knee joint. Conclusion: Clinical studies in awake humans reported that experimentally-induced pain did not affect, or else slightly decreased MSA spontaneous discharge and/or response during weak dorsiflexor muscle contraction, thus failing to support an excitatory nociceptive-fusimotor relationship. However, a majority of pre-clinical studies indicated that ipsilateral and contralateral muscle injection of noxious substances altered MSA resting discharge and/or response to stretch predominately through static fusimotor reflex mechanisms. Methodological differences (use of anesthesia, stretch methodology, etc.) may ultimately be responsible for the discrepancies between clinical and pre-clinical findings. Additional investigative efforts are needed to reconcile these discrepancies and to clearly establish or refute the existence of nociceptive-fusimotor relationship in muscular pain.

Aerobic exercise ameliorates survival, clinical score, lung inflammation, DNA and protein damage in septic mice.

BACKGROUND AND OBJECTIVE: Sepsis is a potentially deadly organic dysfunction, and one of the main causes of mortality in intensive care units (ICU). Aerobic exercise (AE) is a preventive intervention in the establishment of inflammatory conditions, such as chronic lung diseases, but its effects on sepsis remain unclear. Therefore, this study aimed to evaluate the effects of AE on health condition, mortality, inflammation, and oxidative damage in an experimental model of pneumosepsis induced by Klebsiella pneumoniae (K.p). METHODS: Animals were randomly allocated to Control; Exercise (EXE); Pneumosepsis (PS) or Exercise + Pneumosepsis (EPS) groups. Exercised animals were submitted to treadmill exercise for 2 weeks, 30 min/day, prior to pneumosepsis induced by K.p tracheal instillation. RESULTS: PS produced a striking decrease in the health condition leading to massive death (85%). AE protected mice, as evidenced by better clinical scores and increased survival (70%). AE alleviated sickness behavior in EPS mice as evaluated in the open field test, and inflammation (nitrite + nitrate, TNF-α and IL-1ß levels) in broncoalveolar fluid. Catalase activity, oxidative damage to proteins and DNA was increased by sepsis and prevented by exercise. CONCLUSION: Overall, the beneficial effects of exercise in septic animals encompassed a markedly improved clinical score and decreased mortality, along with lower inflammation markers, less DNA and protein damage, as well as preserved antioxidant enzyme activity. Neural network risk analysis revealed exercise had a considerable effect on the overall health condition of septic mice.

Electroacupuncture decreases inflammatory pain through a pro-resolving mechanism involving the peripheral annexin A1-formyl peptide receptor 2/ALX-opioid receptor pathway.

The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.

Post-Match Recovery in Soccer with Far-Infrared Emitting Ceramic Material or Cold-Water Immersion.

We investigated the effects of two common recovery methods; far-infrared emitting ceramic materials (Bioceramic) or cold-water immersion on muscular function and damage after a soccer match. Twenty-five university-level soccer players were randomized into Bioceramic (BIO; n = 8), Cold-water immersion (CWI; n = 9), or Control (CON; n = 8) groups. Heart rate [HR], rating of perceived exertion [RPE], and activity profile through Global Positioning Satellite Systems were measured during the match. Biochemical (thiobarbituric acid reactive species [TBARS], superoxide dismutase [SOD], creatine kinase [CK], lactate dehydrogenase [LDH]), neuromuscular (countermovement [CMJ] and squat jump [SJ], sprints [20-m]), and perceptual markers (delayed-onset muscle soreness [DOMS], and the perceived recovery scale [PRS]) were assessed at pre, post, 24 h, and 48 h post-match. One-way ANOVA was used to compare anthropometric and match performance data. A two-way ANOVA with post-hoc tests compared the timeline of recovery measures. No significant differences existed between groups for anthropometric or match load measures (P > 0.05). Significant post-match increases were observed in SOD, and decreases in TBARS in all groups (p < 0.05), without differences between conditions (p > 0.05). Significant increases in CK, LDH, quadriceps and hamstring DOMS (p < 0.05), as well as decreases in 20-m, SJ, CMJ, and PRS were observed post-match in all groups (p < 0.05), without significant differences between conditions (p > 0.05). Despite the expected post-match muscle damage and impaired performance, neither Bioceramic nor CWI interventions improved post-match recovery.

ET-B receptors involvement in peripheral opioid analgesia induced by light-emitting diode photobiomodulation in male and female mice.

Currently, photobiomodulation therapy (PBMT) is gaining space in the scientific and clinical environment. To help elucidate the importance of irradiance, this study evaluated the effect of two different PBMT irradiances (3.5 and 90 mW/cm2), given a fixed wavelength of 630 nm and a dose of 2 J/cm2, on mechanical hyperalgesia following Complete Freund's Adjuvant (CFA) intraplantar (i.pl.) injection in mice. Additionally, we investigated the role of peripheral opioid and endothelin-B receptors (ETB-R), as well as sex differences in treatment outcome. Different groups of male or female mice were evaluated 6 and 96 h after CFA. Mechanical hyperalgesia was evaluated 30 min after treatments. Naloxone or Bq-788 administration, fifteen minutes before PBMT or Sarafotoxin S6c, helped determine the involvement of peripheral opioid and ETB-Rs on PBMT. Lastly, ETB-Rs skin immunocontent in both sexes was quantified after PBMT consecutive daily treatments. PBMT at an irradiance of 90 mW/cm2, was more effective than 3.5 mW/cm2. Bq-788 and naloxone administration prevented the effects of PBMT and SRTX S6c; however, PBMT did not influence peripheral ETB-Rs immunocontent. The results suggest that irradiance influences PMBT effect; and that activation of ETB-R play a role in peripheral PBMT opioid induced analgesia. Lastly, PMBT effects do not appear to be sex-dependent.

Contribution of the sensory innervation of the spine in low back pain: review and clinical commentary.

Few validated tests allow a precise aetiological diagnosis of Low Back Pain (LBP), and the difficulty of clinical evaluations could be one of the reasons to explain the lack of effectiveness in the therapeutic management of chronic LBP. However, an implication of a sensory impairment in the control of sensorimotor circuits could be suggested. Interactive and specific responses between nociceptive nerve fibres and the paraspinal musculature motor control could have clinical implications, in particular through kinematic evaluation. Following an introduction to the link between the sensory innervation of the spine and pain, we then summarise the maladaptive movement in LBP at the kinematic and neuropathological level. A clinical objectification of these kinematic adaptations at the lumbar spine level, would clarify the aetiological diagnosis causes of chronic LBP, and so help optimising therapeutic strategies by proposing a relevant and precise clinical model of this painful condition.

Role of the endocannabinoid system on the antihyperalgesic action of gabapentin in animal model of neuropathic pain induced by partial sciatic nerve ligation.

Gabapentin has antihyperalgesic action, decreasing central sensitization in neuropathic pain models; this effect depends on the mobilization of endogenous pain control pathways. This study aims to investigate the contribution of the endocannabinoid system to the antihyperalgesic action of gabapentin. Mus musculus Swiss, male, were submitted to PSL. On the 7th and 14th days post PSL, different groups were treated with CB1 receptor antagonist, AM281 via i.t. (2 µg/5 µl) or i.pl. (10 µg/20 µl) or CB2, AM630 via i.t. (5 µL i.t.) or (20 µL i.p.) and 15 min after gabapentin (30 mg / kg orally). Mechanical hyperalgesia was measured by the frequency of paw removal by the von Frey monofilament. Gabapentin demonstrated antihypernociceptive action, which was attenuated in animals pretreated with AM281 in both the i.t. and i.pl routes on the 7th and 14th days, differently from animals pretreated with AM630 that did not achieve a significant reduction with administration i.t. only on the 14th day with administration i.pl. The results show that endocannabinoid system contributes to the antihyperalgesic action of gabapetin in neuropathic pain by PSL, suggesting participation in the medullary and peripheral levels of CB1 receptors, and the peripheral performance of CB2 receptors.

Medium- and long-term functional behavior evaluations in an experimental focal ischemic stroke mouse model.

Cerebrovascular accident (CVA) is one of the leading causes of death and disability worldwide, as well as a major financial burden for health care systems. CVA rodent models provide experimental support to determine possible in vivo therapies to reduce brain injury and consequent sequelae. This study analyzed nociceptive, motor, cognitive and mood functions in mice submitted to distal middle cerebral artery (DMCA) occlusion. Male C57BL mice (n = 8) were randomly allocated to control or DMCA groups. Motor function was evaluated with the tests: grip force, rotarod and open field; and nociceptive threshold with von Frey and hot plate assessments. Cognitive function was evaluated with the inhibitory avoidance test, and mood with the tail suspension test. Evaluations were conducted on the seventh- and twenty-eighth-day post DMCA occlusion to assess medium- and long-term effects of the injury, respectively. DMCA occlusion significantly decreases muscle strength and spontaneous locomotion (p < 0.05) both medium- and long term; as well as increases immobility in the tail-suspension test (p < 0.05), suggesting a depressive-type behavior. However, DMCA occlusion did not affect nociceptive threshold nor cognitive functions (p > 0.05). These results suggest that, medium- and long-term effects of DMCA occlusion include motor function impairments, but no sensory dysfunction. Additionally, the injury affected mood but did not hinder cognitive function.