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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.

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 [CB 1 ] antagonist; 2 µg/5 µl), (3); and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A 1 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, CB 1, and A 1 spinal receptors might contribute to the pain-relieving effect of WWIT., (Copyright © 2020 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Lavandula angustifolia (LaEO) essential oil has been widely used by aromatherapy in the treatment of various clinical conditions, with evidence of its analgesic and anti-inflammatory potential. Our results demonstrate that sixty-five substances were identified in LaEO. Among the compounds found, the major ones were linalool (30.61%) and linalyl acetate (20.36%). We found that LaEO inhalation reduces mechanical hyperalgesia in conditions of chronic inflammatory and neuropathic pain. Furthermore, this effect seems to be mediated by peripheral and central opioid and cannabinoid 2 receptors. The findings of the present study suggests that the LaEO inhalation is effective on the chronic pain treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study evaluated the effects of continuous and interval running on a treadmill on mechanical hyperalgesia in an animal model of chronic postischemia pain and analyzed the mechanism of action of this effect. Different groups of male Swiss mice with chronic postischemia pain, induced by 3 hours of paw ischemia followed by reperfusion, ran on the treadmill in different protocols-the speed (10, 13, 16, or 19 m/min), duration (15, 30, or 60 minutes), weekly frequency (3 or 5 times), weekly increase in continuous and interval running speed-were tested. Mechanical hyperalgesia was evaluated by von Frey filament 7, 14, and 21 days after paw ischemia followed by reperfusion. On day 11 after paw ischemia followed by reperfusion and after 5 days of continuous and interval running, concentrations of cytokines, oxidative stress parameters, and extracellular signal-regulated kinase 1/2 and AKT 1/2/3 expression in the spinal cord were measured. The results showed that continuous running has an antihyperalgesic effect that depends on intensity and volume. Interval running has a longer-lasting antihyperalgesic effect than continuous running. The antihyperalgesic effect depends on intensity and volume in continuous running, and increasing speed maintains the antihyperalgesic effect in both protocols. In the spinal cord, both runs decreased tumor necrosis factor-α and interleukin-6 levels and increased interleukin-10. Both running protocols reduced oxidative damage in the spinal cord. Only interval running had lower concentrations of phosphorylated extracellular signal-regulated kinase 1/2 in the spinal cord. Interval running presented a great antihyperalgesic potential with more promising results than continuous running, which may be owing to the fact that the interval running can activate different mechanisms from those activated by continuous running. PERSPECTIVE: A minimum of .5-hour sessions of moderate to high intensity ≥3 times a week are essential parameters for continuous and interval running-induced analgesia. However, interval running was shown to be more effective than continuous running and can be an important adjuvant treatment to chronic pain., (Copyright © 2018 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: The present study aimed to evaluate the analgesic and anti-inflammatory effects of far infrared-emitting ceramics (cFIRs) in a model of persistent inflammatory hyperalgesia and to elucidate the possible mechanisms of these effects., Methods: Mice were injected with complete Freund's adjuvant (CFA) and treated with cFIRs via placement on a pad impregnated with cFIRs on the bottom of the housing unit for different periods of time. Mice underwent mechanical hyperalgesia and edema assessments, and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-10 levels were measured. Twenty-four hours after CFA injection and 30 min before cFIR treatment, mice were pretreated with a nonselective adenosinergic antagonist, caffeine, the selective adenosine receptor A 1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), the selective cannabinoid receptor type 1 antagonist, AM281, the selective cannabinoid receptor type 2 antagonist, AM630, or the nonselective opioid receptor antagonist, naloxone, and mechanical hyperalgesia was assessed., Results: cFIRs statistically (P < 0.05) decreased CFA-induced mechanical hyperalgesia ((82.86 ± 5.21)% in control group vs (56.67 ± 9.54)% in cFIR group) and edema ((1699.0 ± 77.8) μm in control group vs (988.7 ± 107.6) μm in cFIR group). cFIRs statistically (P < 0.05) reduced TNF-α ((0.478 ± 0.072) pg/mg of protein in control group vs (0.273 ± 0.055) pg/mg of protein in cFIR group) and IL-1β ((95.81 ± 3.95) pg/mg of protein in control group vs (80.61 ± 4.71) pg/mg of protein in cFIR group) levels and statistically (P < 0.05) increased IL-10 ((18.32 ± 0.78) pg/mg of protein in control group vs (25.89 ± 1.23) pg/mg of protein in cFIR group) levels in post-CFA-injected paws. Peripheral pre-administration of inhibitory neuroreceptor antagonists (caffeine, DPCPX, AM281, AM630 and naloxone) prevented the analgesic effects of cFIRs (P < 0.05)., Conclusion: These data provide additional support for the use of cFIRs in the treatment of painful inflammatory conditions and contribute to our understanding of the neurobiological mechanisms of the therapeutic effects of cFIRs., (Copyright © 2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Cedar is part of the phylum of conifers, and it's essential oil has been used for therapeutic purposes since ancient times. In our previous study, we have demonstrated that the inhalation of the Cedrus atlantica essential oil (CaEO) induces an antihyperalgesic effect in a model of postoperative pain. But the mechanism that underlies this effect is not yet fully known., Aim of the Study: This study investigates the involvement of the endocannabinoid system in the antihyperalgesic effect produced by the inhalation of CaEO in a post operative pain model., Materials and Methods: Male Swiss mice (25-35±2g) were subjected to plantar incision. To assess the involvement of the endocannabinoid system, two different approaches were made: (1) by administering antagonists to the CB 1 and CB 2 receptors in different sites (intraperitoneal [i.p.], intraplantar [i.pl.] and intrathecal [i.t.]) and (2) by assessing the synergic effect of the inhalation of sub-effective doses of CaEO, Fatty acid hydrolase (FAAH) and Monoacylglycerol lipase (MAGL), and endocannabinoid degradation inhibitors (URB937 and JZL184, respectively)., Results: The antihyperalgesic effect of CaEO inhalation was prevented by pretreatment with AM281 or AM630 given by i.p. and i.t., but not i.pl. Additionally, in mice pretreated with FAAH or the MAGL inhibitors, the antihyperalgesic effect of CaEO inhalation was significantly longer, which demonstrates the involvement of the endocannabinoid system in the antihyperalgesic effect of CaEO inhalation in a preclinical model of postoperative pain., Conclusions: The present study shows that CaEO inhalation exerts an antihyperalgesic effect, possibly by the activation of the endocannabinoid system in a preclinical model of postoperative pain. It could be a new alternative to treat pain in a clinical environment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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., (© 2015 Peripheral Nerve Society.)