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.

Correction to: Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

The original version of this article contains an error. The Author Francisco José Cidral-Filho incorrectly listed as Francisco José Cidra-Filho. The correct spelling is presented above. The original article has been corrected.

Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ETB) in this effect. Female Swiss mice were subjected to 3 h hind paw ischemia/reperfusion CPIP model. EA treatment produced time-dependent inhibition of mechanical and cold hyperalgesia, as well as edema in CPIP mice. Peripheral administration (i.pl.) of BQ-788 (10 nmol), an ETB antagonist, prevented EA-induced antihyperalgesia while intrathecal administration prolonged EA's effect. Additionally, peripheral pre-treatment with sarafotoxin (SRTX S6c, 30 pmol, ETB agonist) increased EA anti-hyperalgesic effect. Furthermore, the expression of peripheral ETB receptors was increased after EA treatments, as measured by western blot. These results may suggest that EA's analgesic effect is synergic with ETB receptor activation in the periphery, as well as central (spinal cord) ETB receptor blockade. These data support the use of EA as a nonpharmacological approach for the management of CRPS-I, in an adjuvant manner to ETB receptor targeting drugs.

Peripheral neurobiologic mechanisms of antiallodynic effect of warm water immersion therapy on persistent inflammatory pain.

Water immersion is widely used in physiotherapy and might relieve pain, probably by activating several distinct somatosensory modalities, including tactile, pressure, and thermal sensations. However, the endogenous mechanisms behind this effect remain poorly understood. This study examined whether warm water immersion therapy (WWIT) produces an antiallodynic effect in a model of localized inflammation and whether peripheral opioid, cannabinoid, and adenosine receptors are involved in this effect. Mice were injected with complete Freund's adjuvant (CFA; intraplantar; i.pl.). The withdrawal frequency to mechanical stimuli (von Frey test) was used to determine 1) the effect of WWIT against CFA-induced allodynia and 2) the effect of i.pl. preadministration of naloxone (a nonselective opioid receptor antagonist; 5 µg/paw), caffeine (a nonselective adenosine receptor antagonist; 150 nmol/paw), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A1 receptor antagonist; 10 nmol/paw), and AM630 (a selective cannabinoid receptor type 2 antagonist; 4 µg/paw) on the antiallodynic effect of WWIT against CFA-induced allodynia. Moreover, the influence of WWIT on paw inflammatory edema was measured with a digital micrometer. WWIT produced a significant time-dependent reduction of paw inflammatory allodynia but did not influence paw edema induced by CFA. Naloxone, caffeine, DPCPX, and AM630 injected in the right, but not in the left, hind paw significantly reversed the antiallodynic effect of WWIT. This is the first study to demonstrate the involvement of peripheral receptors in the antiallodynic effect of WWIT in a murine model of persistent inflammatory pain.

Caffeine prevents antihyperalgesic effect of gabapentin in an animal model of CRPS-I: evidence for the involvement of spinal adenosine A1 receptor.

This study was designed to determine whether 3 weeks of gabapentin treatment is effective in alleviating neuropathic pain-like behavior in animal models of complex regional pain syndrome type-I and partial sciatic nerve ligation (PSNL). We investigated the contribution of adenosine subtypes to the antihyperalgesic effect of gabapentin by examining the effect of caffeine, a non-selective adenosine A1 and A2 receptor antagonist or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 subtype receptor antagonist on this effect. Neuropathic pain was produced by unilateral prolonged hind paw ischemia and reperfusion (I/R) or PSNL procedures which resulted in stimulus-evoked mechanical hyperalgesia. After procedures, animals received gabapentin (10, 30, or 100 mg/kg intraperitoneal, respectively), caffeine (10 mg/kg intraperitoneal or 150 nmol intrathecally) or DPCPX (3 µg intrathecally) alone or in combination. Mice were tested for tactile mechanical hyperalgesia at 1, 2, and 3 weeks following procedures. Gabapentin produced dose-related inhibition of mechanical hyperalgesia over a 3-week period, and this effect was blocked by concomitant caffeine or DPCPX administration 1 week after injuries. The results of this study demonstrated that the mechanism through which gabapentin produces its effect may involve the activation of adenosine A1 subtype receptor.

Light-emitting diode therapy induces analgesia in a mouse model of postoperative pain through activation of peripheral opioid receptors and the L-arginine/nitric oxide pathway.

Light-emitting diode therapy (LEDT) has been clinically used as an alternative to low-level laser therapy; nevertheless, the molecular basis for LEDT effects remains unclear. The objective of this study was to evaluate the analgesic effect of LEDT in the mouse plantar incision (PI) model of postoperative pain, as well as to investigate some of the possible mechanisms involved in this effect, i.e., peripheral and central opioid receptors; migration of opioid-containing leukocytes to PI site and the L-arginine/nitric oxide (NO) pathway. To that end, mice were subjected to PI and treated with LEDT (950 nm, 80 mW/cm(2), 1 through 13 J/cm(2)). Mechanical hypersensitivity was assessed as withdrawal frequency percentage to 10 presentations of a 0.4-g von Frey filament. In addition, the animals were pretreated with systemic (i.p.), intra-plantar (i.pl.), or intrathecal injection (i.t) of naloxone (a nonselective opioid receptor antagonist; 1 mg/kg, i.p.; 5 µg/right paw or 5 µg/site, respectively) or a systemic injection of fucoidin (100 µg/mouse, i.p., an inhibitor of leukocyte rolling through binding to L- and P-selectins). Our results demonstrate, for the first time, that LEDT induced a dose-response analgesic effect in the model of PI in mice. At the dose of 9 J/cm(2) LEDT presented the most significant results through (1) activation of peripheral opioid receptors which involve, at least partially, the recruitment of opioid-containing leukocytes to the PI site and; (2) activation of the L-arginine/NO pathway. These results extend previous literature data and suggest that LEDT might be useful in the treatment of postoperative pain.

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.

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.

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.

Ankle joint mobilization decreases hypersensitivity by activation of peripheral opioid receptors in a mouse model of postoperative pain.

OBJECTIVE: Investigate whether ankle joint mobilization (AJM) decreases hypersensitivity in the mouse plantar incision (PI) model of postoperative pain as well as to analyze the possible mechanisms involved in this effect. DESIGN: Experiment 1: PI male Swiss mice (25-35 g, N = eight animals per group) were subjected to five sessions of AJM, each lasting either 9 or 3 minutes. AJM movement was applied at a grade III as defined by Maitland. Paw withdrawal frequency to mechanical stimuli was assessed before realization of PI and before and after daily AJM sessions. Mechanical hypersensitivity was also assessed following systemic (intraperitoneal [i.p.]) and local (intraplantar) injection of naloxone (a nonselective opioid receptor antagonist; 1 mg/kg, i.p.; 5 µg/paw, respectively, experiment 2); and systemic injection of fucoidin (100 µg/mouse, i.p., an inhibitor of leukocyte rolling, experiment 3) in different groups of mice. RESULTS: Nine but not 3 minutes of AJM reduced mechanical hypersensitivity caused by PI, an effect that was prevented by systemic and local administrations of naloxone but not by fucoidin. CONCLUSIONS: Our results indicate that joint mobilization reduces postoperative pain by activation of the peripheral opioid pathway. However, antihypersensitivity induced by AJM is apparently not limited by the number of opioid-containing leukocytes but by opioid receptors availability in sensory neurons. A better understanding of the peripheral mechanisms of AJM could stimulate therapists to integrate joint mobilization with strategies also known to influence endogenous pain control, such as exercise, acupuncture, and transcutaneous electrical nerve stimulation to potentiate endogenous analgesia.

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 spinal inhibitory neuroreceptors in the antihyperalgesic effect of warm water immersion therapy.

OBJECTIVE: Warm water immersion therapy (WWIT) has been widely used in the treatment of various clinical conditions, with analgesic and anti-inflammatory effects. However, its mechanism of action has not been fully investigated. The present study analyzed the role of spinal inhibitory neuroreceptors in the antihyperalgesic effect of WWIT in an experimental model of inflammatory pain. METHODS: Mice were injected with complete Freund's adjuvant (CFA; intraplantar [i.pl.]). Paw withdrawal frequency to mechanical stimuli (von Frey test) was used to determine: (1) the effect of intrathecal (i.t.) preadministration of naloxone (a non-selective opioid receptor antagonist; 5 µg/5 µl), (2); AM281 (a selective cannabinoid receptor type 1 [CB1] antagonist; 2 µg/5 µl), (3); and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A1 receptor antagonist; 10 nmol/5 µl), on the antihyperalgesic (pain-relieving) effect of WWIT against CFA-induced hyperalgesia. RESULTS: Intrathecal naloxone, AM281, and DPCPX significantly prevented the antihyperalgesic effect of WWIT. This study suggests the involvement of spinal (central) receptors in the antihyperalgesic effect of WWIT in a model of inflammatory pain. CONCLUSIONS: Taken together, these results suggest that opioid, CB1, and A1 spinal receptors might contribute to the pain-relieving effect of WWIT.

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.

Aquatic exercise and Far Infrared (FIR) modulates pain and blood cytokines in fibromyalgia patients: A double-blind, randomized, placebo-controlled pilot study.

Fibromyalgia (FM) has an inflammatory component, as elevated serum levels of inflammatory biomarkers are associated with its diagnosis. Treatments decreased pain, body temperature, improved quality of life and reduced serum levels of IL-6 in both groups; however, these beneficial effects were more pronounced in aquatic exercise (AE) + Far-Infrared (FIR) group. The findings of the present study suggest that the association of AE to FIR increases the benefits of aquatic exercise in patients with FM.

Manual Therapy Reduces Pain Behavior and Oxidative Stress in a Murine Model of Complex Regional Pain Syndrome Type I.

Complex regional pain syndrome type I (CRPS-I) is a chronic painful condition. We investigated whether manual therapy (MT), in a chronic post-ischemia pain (CPIP) model, is capable of reducing pain behavior and oxidative stress. Male Swiss mice were subjected to ischemia-reperfusion (IR) to mimic CRPS-I. Animals received ankle joint mobilization 48h after the IR procedure, and response to mechanical stimuli was evaluated. For biochemical analyses, mitochondrial function as well as oxidative stress thiobarbituric acid reactive substances (TBARS), protein carbonyls, antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) levels were determined. IR induced mechanical hyperalgesia which was subsequently reduced by acute MT treatment. The concentrations of oxidative stress parameters were increased following IR with MT treatment preventing these increases in malondialdehyde (MDA) and carbonyls protein. IR diminished the levels of SOD and CAT activity and MT treatment prevented this decrease in CAT but not in SOD activity. IR also diminished mitochondrial complex activity, and MT treatment was ineffective in preventing this decrease. In conclusion, repeated sessions of MT resulted in antihyperalgesic effects mediated, at least partially, through the prevention of an increase of MDA and protein carbonyls levels and an improvement in the antioxidant defense system.

Pain-related encephalic regions influenced by yoga meditation: An integrative review.

INTRODUCTION: The mechanisms underlying the use of yoga in pain relief are still unclear. This study reviewed literature reports on encephalic activity related to analgesia induced by yoga meditation practice. METHODS: This integrative review examined studies published in the Pubmed, LILACS and MEDLINE databases without restriction of the year of publication. The research involved 16 descriptors related to the words: yoga, pain and neuroimaging methods. Inclusion criteria involved only the publications available online, with free access and written in English. RESULTS: 2 case studies and 1 pilot study met the criteria. Yoga meditation practice induces analgesia primarily through attenuation of the medial pain perception system including the Anterior Cingulate Cortex and Insula regions, as well as the lateral system including the Secondary Sensory Cortex and Thalamus. CONCLUSION: Yoga induced analgesia is a potentially important adjunct to current pain management. This integrative review revealed that there is a need for further research that analyzes the encephalic regions related to analgesia induced by yoga practice.

Long-Term Regular Eccentric Exercise Decreases Neuropathic Pain-like Behavior and Improves Motor Functional Recovery in an Axonotmesis Mouse Model: the Role of Insulin-like Growth Factor-1.

Although training programs with regular eccentric (ECC) exercise are more commonly used for improving muscular strength and mobility, ECC exercise effects upon functional recovery of the sciatic nerve has not yet been determined. After sciatic nerve crush, different mice groups were subjected to run on the treadmill for 30 min at a speed of 6, 10, or 14 m/min with - 16° slope, 5 days per week, over 8 weeks. During the training time, neuropathic pain-like behavior (mechanical and cold hyperalgesia) was assessed and functional recovery was determined with the grip strength test and the Sciatic Functional and Static indexes (SFI and SSI). After 9 weeks, triceps surae muscle weight and morphological alterations were assessed. Tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-1Ra (IL-1Ra), insulin-like growth factor-1 (IGF-1) levels, and markers pro- and anti-inflammatory and regeneration, respectively, were quantified in the muscle and sciatic nerve on day 14 post-crushing. Exercised groups presented less neuropathic pain-like behavior and better functional recovery than non-exercised groups. Biochemically, ECC exercise reduced TNF-α increase in the muscle. ECC exercise increased sciatic nerve IGF-1 levels in sciatic nerve crush-subjected animals. These findings provide new evidence indicating that treatment with ECC might be a potential approach for neuropathy induced by peripheral nerve injury.

Inhalation of Cedrus atlantica essential oil alleviates pain behavior through activation of descending pain modulation pathways in a mouse model of postoperative pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Cedrus atlantica essential oil (CaEO) presents analgesic and anti-inflammatory sedative properties. However, it remains unknown whether CaEO alleviates acute postoperative pain. MATERIALS AND METHODS: Here, we investigated the effect of CaEO on postoperative pain and its mechanisms related to the descending pain control in Swiss males mice induced by a plantar incision surgery (PIS) in the hindpaw. RESULTS: Inhalation of CaEO (5', 30' or 60') markedly reduced mechanical hypersensitivity. This effect was prevented by pre-treatment with naloxone or p-chlorophenylalanine methyl ester (PCPA, 100mg/kg, i.p.)-induced depletion of serotonin. In addition, p-alpha-methyl-para-tyrosin (AMPT, 100mg/kg, i.p.)-induced depletion of norepinephrine, intraperitoneal injection of the α2-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or haloperidol (1mg/kg, i.p.) an antagonist of dopaminergic (D1 and D2) receptors prevented the effect of CaEO on hypersensitivity. CONCLUSIONS: These findings suggest that CaEO alleviates postoperative pain by activating the descending pain modulation pathways on the opioidergic, serotonergic, noradrenergic (α2-adrenergic) and dopaminergic (dopamine D1 and D2 receptors) systems.

Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL-10 µL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1ß, TNF-α, IL-6, INF-Ï«, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1ß (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-Ï« (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice.

Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain.

Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain.