Electroacupuncture alleviates the transition from acute to chronic pain through the p38 MAPK/TNF-α signalling pathway in the spinal dorsal horn.

BACKGROUND: Hyperalgesic priming (HP) is a model of the transition from acute to chronic pain. Electroacupuncture (EA) could inhibit pain development through the peripheral dorsal root ganglia; however, it is unclear whether it can mitigate the transition from acute to chronic pain by attenuating protein expression in the p38 MAPK (mitogen-activated protein kinase)/tumour necrosis factor alpha (TNF-α) pathway in the spinal dorsal horn. AIMS: We aimed to determine whether EA could prevent the transition from acute to chronic pain by affecting the p38 MAPK/TNF-α pathway in the spinal dorsal horn in a rat model established using HP. METHODS: We first randomly subdivided 30 male Sprague-Dawley (SD) rats into 5 groups (n = 6 per group): control (N), sham HP (Sham-HP), HP, HP + SB203580p38 MAPK (HP+SB203580), and HP + Lenalidomide (CC-5013) (HP+Lenalidomide). We then randomly subdivided a further 30 male SD rats into 5 groups (n = 6 per group): Sham-HP, HP, sham EA (Sham EA), EA (EA), and EA + U-46619 p38 MAPK agonist (EA+U-46619). We assessed the effects of EA on the mechanical paw withdrawal threshold and p38 MAPK/TNF-α expression in the spinal dorsal horn of rats subjected to chronic inflammatory pain. RESULTS: Rats in the EA group had reduced p38 MAPK and TNF-α expression and had significantly reduced mechanical hyperalgesia compared with rats in the other groups. CONCLUSION: Our findings indicate that EA could increase the mechanical pain threshold in rats and inhibit the transition from acute pain to chronic pain. This mechanism could involve reduced p38 MAPK/TNF-α expression in the spinal dorsal horn.

Topical and systemic use of Joannesia princeps vell. LC seed oil in acute pain and inflammation induced by different agents.

ETHNOPHARMACOLOGICAL RELEVANCE: Joannesia princeps (SOJP) has been used in folk medicine as anthelmintic treatment and cutaneous wound healing. AIM OF THE STUDY: The purpose of this study is to evaluate the pharmacological activity of seed oil of Joannesia princeps, administered systemically and topically, on acute pain and inflammation. MATERIALS AND METHODS: Male swiss mice were treated orally and topically with seed oil of Joannesia princeps in models of acute pain (acetic acid-induced abdominal writhing, formalin-induced licking behaviour and tail flick tests) and acute inflammation (carrageenan- and histamine-induced paw oedema; arachidonic acid-, capsaicin- and croton oil-induced ear oedema and air pouch tests), besides the open field model in the motor performance evaluation. RESULTS: Seed oil of Joannesia princeps showed systemic action against acute pain in abdominal writhing test (37% and 56% inhibition in the number of writhes at doses of 30 and 100 mg/kg, respectively) and in the second phase of formalin-induced licking behaviour test (29%, 47 and 52% inhibition in the licking time at doses of 10, 30 and 100 mg/kg, respectively), as well as reducing croton oil-induced ear oedema by 72%, leukocyte recruitment and production of TNF-α and IL-6 in the air pouch tests. In addition, topical administration of SOJP inhibited carrageenan-induced paw oedema by 39% at dose of 500 µg/paw and inhibited histamine-induced oedema by 43 and 52% at doses of 300 and 500 µg/paw, respectively. SOJP also decreased croton oil-induced ear oedema by 67% at dose of 500 µg/paw and arachidonic acid-induced ear oedema by 63% at dose of 500 µg/paw, reducing the production of TNF-α, IL-1ß and MIP2 in both. In addition, no adverse effects were observed at doses up to 2000 mg/kg. CONCLUSIONS: Seed oil of Joannesia princeps presents antinociceptive and anti-inflammatory actions through its topical and systemic administration, promoted by inhibition of leukocyte recruitment and cytokine production (TNF-α, IL-1ß, IL-6 and MIP-2).

The Effects of Acute Neonatal Pain on Expression of Corticotropin-Releasing Hormone and Juvenile Anxiety in a Rodent Model.

Premature infants in the neonatal intensive care unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects' left plantar paw surface which occurred four times daily during the first week of life [postnatal day (PND)1-PND7]. Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND6) and fluorescent in situ hybridization (FISH) for corticotropin-releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND24 and PND25) and underwent innate anxiety testing utilizing an elevated plus maze (EPM) protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage.

The efficacy of muscle energy techniques in symptomatic and asymptomatic subjects: a systematic review.

Background: Muscle energy techniques are applied to reduce pain and increase range of motion. These are applied to a variety of pathological conditions and on asymptomatic subjects. There is however limited knowledge on their effectiveness and which protocol may be the most beneficial. Objective: The aim of this review is to determine the efficacy of muscle energy techniques (MET) in symptomatic and asymptomatic subjects. Design: Systematic Review. Methods: A literature search was performed using the following database: Cochrane Library, MEDLINE, NLM Pubmed and ScienceDirect. Studies regarding MET in asymptomatic and symptomatic patients were considered for investigation. The main outcomes took into account range of motion, chronic and acute pain and trigger points. Two trained investigators independently screened eligible studies according to the eligibility criteria, extracted data and assessed risk of bias. Randomized control trials (RCT's) were analyzed for quality using the PEDro scale. Results: A total of 26 studies were considered eligible and included in the quantitative synthesis: 14 regarding symptomatic patients and 12 regarding asymptomatic subjects. Quality assessment of the studies through the PEDro scale observed a "moderate to high" quality of the included records. Conclusions: MET are an effective treatment for reducing chronic and acute pain of the lower back. MET are also effective in treating chronic neck pain and chronic lateral epicondylitis. MET can be applied to increase range of motion of a joint when a functional limitation is present. Other techniques seem to be more appropriate compared to MET for trigger points.

Oral treatment with essential oil of Hyptis spicigera Lam. (Lamiaceae) reduces acute pain and inflammation in mice: Potential interactions with transient receptor potential (TRP) ion channels.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Hyptis comprehends almost 400 species widespread in tropical and temperate regions of America. The use of Hyptis spicigera Lam. (Lamiaceae) is reported in traditional medicine due to its gastroprotective, anti-inflammatory and analgesic properties. AIM OF THE STUDY: The rationale of this study was to investigate the potential use of the essential oil of H. spicigera (EOHs) as analgesic. MATERIAL AND METHODS: The antinociceptive effect of EOHs was verified analyzing acute nocifensive behavior of mice induced by chemical noxious stimuli [i.e., formalin and transient receptor potential (TRP) channels agonists]. We also verified the effects of EOHs on locomotor activity and motor performance in mice. Finally, we investigate the involvement of central afferent C-fibers with EOHs analgesic effect. RESULTS: EOHs presented antinociceptive effect at 300 and 1000mg/kg on formalin-induced pain behavior model, presenting 50% and 72% of inhibition during the first phase (ED50 =292mg/kg), and 85% and 100% during de second phase (ED50 =205mg/kg), respectively. Temperature of the hind paw was reduced by EOHs treatment in a dose-dependent manner; oedema was diminished only by EOHs 1000mg/kg. EOHs does not impaired locomotor activity or motor performance. For mice injected with capsaicin, a TRPV1 activator, EOHs (1000mg/kg, ED50 =660mg/kg) showed decreased (63%) nociceptive behavior. When injected with cinnamaldehyde (TRPA1 activator), mice treated with EOHs showed 23%, 43% and 66% inhibition on nociceptive behavior (100, 300 and 1000mg/kg, respectively; ED50 402mg/kg). When mice were injected with menthol (TRPM8 activator), EOHs showed 29%, 59% and 98% inhibition of nociceptive behavior (100, 300 and 1000mg/kg, respectively; with ED50 =198mg/kg. Finally, when desensitized mice were injected with menthol, EOHs (300mg/kg) does not show antinociceptive effect. CONCLUSIONS: This study demonstrated the efficacy of EOHs on experimental models of nociception. We have found the involvement of TRP channels V1, A1 and M8 with EOHs activity, which was remarkably potent and efficient in inhibiting pain evoked by menthol, a TRPM8 channel activator. TRPM8 channels from TRPV1+ C-fibers, but not TRPM8+ C-fibers nor TRPM8+ Aδ mechanosensory fibers, mediate EOHs analgesic effects.

Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor.

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.

The antinociceptive properties of the novel compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one in acute pain in mice.

The compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one [(±)-δ-lactone] was isolated from the plant Vitex cymosa Bertero, and determined to be the active principle. The present study aimed to evaluate the antinociceptive effect of (±)-δ-lactone and to elucidate its mechanism of action. Mice were subjected to in-vivo models of acute pain (acetic acid-induced abdominal writhing, formalin and hot-plate tests) and the open-field test. (±)-δ-Lactone, administered orally (6-900 µmol/kg), exerted a dose-dependent antinociceptive effect in the acetic acid-induced abdominal writhing, formalin and hot-plate tests. (±)-δ-Lactone administered by the intrathecal (i.t.) and subplantar (s.p.) routes (10-600 nmol) exerted concentration-dependent antinociceptive effects in the formalin test, showing its spinal and peripheral activity, respectively. In the hot-plate test, (±)-δ-lactone was also active when administered i.t., confirming its spinal effect. The previous intraperitoneal (i.p.) application of naloxone, yohimbine, mecamylamine or glibenclamide did not alter the effect produced by the i.t. administration of (±)-δ-lactone, whereas the previous application of atropine and L-arginine significantly reduced its effects in the formalin and hot-plate tests. The previous i.p. application of L-NAME enhanced the antinociceptive effect of the i.t. administration of (±)-δ-lactone in the formalin and hot-plate tests. The previous i.p. application of L-NAME and L-arginine increased and decreased, respectively, the activity of (±)-δ-lactone administered by s.p. administration. These results indicate that (±)-δ-lactone has significant spinal and peripheral antinociceptive activity, and that its effects are at least partially mediated by a reduced nitric oxide production/release, most likely through mechanisms involving the cholinergic system.