Maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus.

Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal's sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress.

Single Cupping Thearpy Session Improves Pain, Sleep, and Disability in Patients with Nonspecific Chronic Low Back Pain.

The objective of this study was to evaluate if a single session of real or placebo cupping therapy in patients with chronic low back pain would be enough to temporarily reduce pain intensity and functional disability, enhancing their mechanical threshold and reducing local skin temperature. The outcome measures were Brief Pain Inventory, pressure pain threshold, Roland-Morris disability questionnaire and low back skin temperature. This is an experimental clinical trial; after examination (AV0), patients were submitted to real or placebo cupping therapy (15 minutes, bilaterally at the points BL23 (Shenshu), BL24 (Qihaishu) and BL25 (Dachangshu) and were revaluated immediately after the session (AV1) and after one week (AV2). The patients showed a significant improvement in all pain severity items and sleep in the Brief Pain Inventory (p < 0.05) and a decrease in disability in Roland-Morris disability questionnaire (p < 0.001). No significant differences were found in pressure pain threshold or skin temperature. No significant differences were found in any outcome of the placebo cupping therapy group. Thus, the cupping therapy is effective in reducing low back pain and decreasing disability after one single session but not in changing skin mechanical threshold or temperature.

On the Right to Science: Recommendations of Selection Criteria for IMIA Scientific Meetings.

The International Medical Informatics Association (IMIA), a non-governmental, not-for-profit, global organization promoting health and biomedical informatics, is committed to the right of communities/populations and individuals to science, comprised of three separate constituent rights: 1) the right to participate in science, 2) the right to benefit from science, and 3) the right to benefit from a person's own contribution to science or inventions. As such, IMIA provides a global platform where scientists, researchers, health information users, vendors, developers, consultants, health care consumers, and suppliers can meet in an environment of cooperation and sharing. In the context of IMIA's conferences, the IMIA board has discussed and identified the important central factors, which are essential considerations to host a scientific meeting. These factors will be used to help vet future contenders applying for the honor to host an IMIA conference: Reasonable safety and security, commitment by the host member society, freedom of travel, scientific freedom, and freedom from discrimination.

Analgesic Effects Elicited by Neuroactive Mediators Injected into the ST 36 Acupuncture Point on Inflammatory and Neuropathic Pain in Mice.

The present study evaluates whether the injection of serotonin, acetylcholine, glutamate, bradykinin, histamine, or substance P (SP) into the Zusanli (Stomach 36, ST 36) acupoint can also produce the acupuncture-induced antinociceptive effect on inflammatory or neuropathic pain. In this in vivo experimental study, a total of 450 male Swiss mice were used. Mice were injected with saline or complete Freund's adjuvant (CFA) or subjected to sham or chronic constriction injury (CCI) surgery. After the establishment of the inflammatory (4 hours) or the neuropathic pain (3 days), the animals (n = 6) received manual acupuncture, sham acupuncture, or injection of saline, serotonin, acetylcholine, glutamate, bradykinin, histamine, or SP into the ST 36 and were evaluated for up to 24 hours. Mechanical threshold was evaluated, and the L4-L6 dorsal root ganglion was used for analysis of the transient receptor potential vanilloid type 1 overexpression. The mice from both the CFA and CCI models treated with manual acupuncture had significant increases in the thresholds for more than 24 hours. Sham acupuncture stimulation did not change the thresholds. In the mice injected with each of the mediators, the thresholds were significantly increased for all times in both the CFA and CCI models. Transient receptor potential vanilloid type 1 overexpression in CFA and CCI mice was reduced at all times by injection of serotonin, acetylcholine, or SP but not by injection of glutamate, histamine, or bradykinin. Our data suggest that the neuroactive mediators released by acupuncture-induced tissue injury may contribute to acupuncture-induced analgesia.

3-Hydroxy-piperidinyl-N-benzyl-acyl-arylhydrazone derivatives reduce neuropathic pain and increase thermal threshold mediated by opioid system.

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.

Single or Multiple Electroacupuncture Sessions in Nonspecific Low Back Pain: Are We Low-Responders to Electroacupuncture?

The objective of this study was to compare the effects of one or multiple sessions of electroacupuncture (EA) in patients with chronic low back pain. The outcome measures were visual analog score (VAS), pressure pain threshold (PPT), McGill pain questionnaire (MPQ), Roland Morris disability questionnaire (RMDQ), low back skin temperature, surface electromyography of longissimus muscle (contraction/rest) and blood cytokines. After examination (AV0), patients were submitted to EA (2 Hz, 30 minutes, bilaterally at the SP6, BL23, BL31, BL32, BL33, and BL60) and were revaluated after one week (AV1). Patients with VAS <3 (VAS <3 group, n = 20) were directed to return after three weeks (AV2). Patients with VAS >3 (VAS >3 group, n = 20) were submitted to one weekly EA-treatment and revaluated after three weeks (AV2). The VAS <3 group showed a significant reduction in VAS and MPQ and increased PPT in AV1, but not in AV2. No significant differences were found in RMDQ. The VAS >3 group showed reduction in VAS and increased PPT in AV1 and a reduction in MPQ and RMDQ only in AV2. No significant differences were found in electromyography, temperature or cytokines. Thus, despite 2Hz-EA is effective reducing low back pain, some patients only experienced reduced pain intensity and improved functional capacity after full treatment.

Antinociceptive effects of low-level laser therapy at 3 and 8 j/cm2 in a rat model of postoperative pain: possible role of endogenous Opioids.

Low-level laser therapy (LLLT) is the direct application of light to stimulate cell responses (photobiomodulation) to promote tissue healing, reduce inflammation, and induce analgesia; the molecular basis for these effects of LLLT remains unclear. The objective of this study was to evaluate the analgesic effect of LLLT in the rat plantar incision model of postoperative pain as well as to investigate some of the possible mechanisms involved in this effect. Wistar rats were submitted to plantar incision and treated with LLLT (830 nm, continuous-mode, 30 mW/cm2 , 1-12 J/cm2 ). Postoperative thermal and mechanical hypersensitivity were monitored for 24 hours post-incision. In addition, the animals were pretreated with saline, naloxone (a nonselective opioid receptor antagonist; 20 µg/5 µl) or methysergide (5-HT2C , 5-HT2A , 5-HT7 , 5-HT5a , 5-HT6, and 5-HT1F receptors antagonist; 30 µg/5 µl). Moreover, 24 hours after incision and treatment, the TNF-α and IL-1ß levels in serum were evaluated. Our results demonstrate, for the first time, that LLLT at 3 or 8 J/cm2 , but not at 1-2, 4-7, or 9-12 J/cm2 , induced an analgesic effect on postoperative pain. Naloxone, but not methysergide, blocked the LLLT-induced anti-nociceptive effect. Additionally, IL-1-ß and TNF-α production significantly decreased after LLLT at 3 or 8 J/cm2 . Our results suggest that LLLT at 3 or 8 J/cm2 primarily modulates the endogenous opioids system and is not directly mediated by serotonergic receptors. Reduction of IL-1ß and TNF-α may play a role in the antinociceptive action of LLLT. Lasers Surg. Med. 49:844-851, 2017. © 2017 Wiley Periodicals, Inc.

Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease.

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 µM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.

Analgesia induced by 2- or 100-Hz electroacupuncture in the rat tail-flick test depends on the anterior pretectal nucleus.

AIMS: The anterior pretectal nucleus (APtN) and electroacupuncture (EA) activate descending mechanisms to modulate nociceptive inputs in the spinal dorsal horn. This study examines qualitatively whether mechanisms in the APtN participate in the EA-induced analgesia in rats. MAIN METHODS: The tail-flick test was utilized to examine the changes produced by non-selective antagonists of serotonergic (methysergide, 37 pg), muscarinic (atropine, 10 ng) and opioid (naloxone, 10 ng) receptors; selective antagonists against µ (CTOP, 6.4 µg), δ (ICI174,864, 6.9 µg) or κ (nor-BNI, 7.3 µg); 5HT1 (methiothepin, 0.47 µg), 5HT2 (ketanserin, 5.4 µg), or 5HT3 (MDL 72222, 15.7 µg); and GABAA (bicuculline, 150 ng) receptors injected into the dorsal (d) or ventral (v) APtN on the antinociception induced by a 20-min EA applied at 2- or 100-Hz frequency to the Zusanli and Sanyinjiao acupoints. KEY FINDINGS: The 2-Hz EA-induced analgesia was blocked by naloxone, CTOP or atropine, was less intense after bicuculline, was shorter after methysergide or methiothepin in dAPtN, and was less intense after methysergide, methiothepin and bicuculline in vAPtN. The 100-Hz EA-induced analgesia was less intense after methysergide, methiothepin and CTOP in vAPtN, and remained unchanged after injection of the antagonists into the dAPtN. SIGNIFICANCE: The 2-Hz EA-induced analgesia utilizes cholinergic muscarinic, µ-opioid, GABAA and 5-HT1 mechanisms in the dAPtN and µ-opioid and 5-HT1 mechanisms in the vAPtN, while 100-Hz EA-induced analgesia utilizes µ-opioid and 5-HT1 mechanisms in the vAPtN but does not utilize them in the dAPtN.

The antinociceptive effect of electroacupuncture at different depths of acupoints and under the needling surface.

BACKGROUND: The stimulation of acupoints along the meridians, but not the non-acupoints outside of the meridians, produces analgesia. Although the acupoint is defined at the body surface, the exact location of the acupoints is not known. This study aims to examine whether the intensity and duration of the analgesic effect of electroacupuncture (EA) at the Zusanli (ST36) and Sanynjiao acupoints (SP6) change according to the depth of the stimulation. METHODS: Ninety-six male Wistar rats classified as responders were arbitrarily allocated into 16 groups of six rats each. Six groups received EA with uninsulated acupuncture needles (type I) or needles that were immersed in varnish and had the varnish circularly peeled 0.2 mm from the tip (type II), 0.2 mm at 3 mm (type III) or 5 mm (type IV) from the tip, or 0.2 mm at 5 and 1 mm from the tip (type V), or EA sham for 20 min. Five groups received injection of formalin into the acupoint bilaterally at 5 mm or 1 mm deep into ST36, 5 mm below ST36 but inserting the needle at 45° to the skin surface, or 5 mm deep into non-acupoints. The remaining groups received intraplantar injection of saline, 1% or 2.5% formalin. The analgesic effects were measured by the rat tail-flick test. RESULTS: The bilateral stimulation of ST36 and SP6 by uninsulated or insulated needles produced analgesia in the rat tail-flick test. The stronger and longer lasting effects occurred after EA with the types I and V needles, or injection of formalin 5 mm deep into ST36. The remaining needles produced weaker and shorter lasting effects. Slow analgesic effect also occurred after formalin injection at 1 mm or 5 mm below ST36 by inserting the needle at 45° to the skin surface. CONCLUSION: The experimental results suggest that the efficacy of the EA stimulation depends on the spatial distribution of the current density under the needling surface rather than only the acupoint or the depth of needling.

Retrosplenial cortex is involved in analgesia induced by 2- but not 100-Hz electroacupuncture in the rat tail-flick test.

This study examined whether or not the antinociceptive effect of 2- or 100-Hz electroacupuncture (EA) depends on the integrity of the retrosplenial cortex (RSC). Rats were taken for determination of tail-flick latency before and after injection of saline or 2% lidocaine (0.25 µl) into the retrosplenial cortex (RSC) bilaterally. Five minutes later, they were submitted to a 20-minute period of 2 Hz, 100 Hz, or sham EA at the Zusanli and Sanyinjiao acupoints bilaterally, and tail-flick latency was measured within 30 seconds after the end of stimulation and at 5-minute intervals for up to 30 minutes. EA at a frequency of either 2 or 100 Hz induced a strong and long-lasting inhibition of the tail-flick reflex in rats treated with saline (0.25 µl) injected into the RSC. The analgesia produced by 2-Hz EA lasted for a shorter time in lidocaine-treated rats. By contrast, RSC impairment did not change the analgesic effect of 100 Hz EA. The integrity of the RSC is implicated in the duration of analgesia induced by low-frequency EA but is not essential for the analgesic effects evoked by high-frequency EA.

Analgesia induced by 2- or 100-Hz electroacupuncture in the rat tail-flick test depends on the activation of different descending pain inhibitory mechanisms.

UNLABELLED: We evaluated the effectiveness of intrathecal antagonists of α1- (WB4101) and α2- (idazoxan) adrenoceptors and serotonergic (methysergide), opioid (naloxone), muscarinic (atropine), GABA(A) (bicuculline) and GABA(B) (phaclofen) receptors in blocking 2- or 100-Hz electroacupuncture (EA)-induced analgesia (EAIA) in the rat tail-flick test. EA was applied bilaterally to the Zusanli and Sanyinjiao acupoints in lightly anesthetized rats. EA increased tail-flick latency, where the effect of 2-Hz EA lasted longer than that produced by 100-Hz EA. The 2-Hz EAIA was inhibited by naloxone or atropine, was less intense and shorter after WB4101 or idazoxan, and was shorter after methysergide, bicuculline, or phaclofen. The 100-Hz EAIA was less intense and shorter after naloxone and atropine, less intense and longer after phaclofen, shorter after methysergide or bicuculline, and remained unchanged after WB4101 or idazoxan. We postulate that the intensity of the effect of 2-Hz EA depends on noradrenergic descending mechanisms and involves spinal opioid and muscarinic mechanisms, whereas the duration of the effect depends on both noradrenergic and serotonergic descending mechanisms, and involves spinal GABAergic modulation. In contrast, the intensity of 100-Hz EAIA involves spinal muscarinic, opioid, and GABA(B) mechanisms, while the duration of the effects depends on spinal serotonergic, muscarinic, opioid, and GABA(A) mechanisms. PERSPECTIVE: The results of this study indicate that 2- and 100-Hz EA induce analgesia in the rat tail-flick test activating different descending mechanisms at the spinal cord level that control the intensity and duration of the effect. The adequate pharmacological manipulation of such mechanisms may improve EA effectiveness for pain management.

The integrity of the anterior pretectal nucleus and dorsolateral funiculus is necessary for electroacupuncture-induced analgesia in the rat tail-flick test.

Previous studies have indicated that the anterior pretectal nucleus (APtN) is implicated in pathways that descend through the dorsolateral funiculus (DLF) to modulate nociceptive inputs in the spinal dorsal horn. The activation of descending inhibitory mechanisms also seems to be involved in electroacupuncture (EA)-induced analgesia. This study utilized the tail-flick test to examine the changes produced by DLF lesion or injection of 2% lidocaine into the APtN in the analgesia induced by 2 or 100 Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints in lightly anesthetized rats. Tail-flick latency was significantly increased by EA, the effect of 2 Hz EA lasting longer than that produced by 100 Hz EA. The effect of either 2 or 100 Hz EA did not occur in DLF lesion rats. The effect of 2 Hz EA did not occur in rats with neural block of the whole or dorsal APtN. In contrast, the effect of 100 Hz EA was reduced in rats with neural block of the whole APtN, but remained unchanged in rats with neural block of the dorsal APtN. We thus conclude that the integrity of the APtN and DLF is necessary for EA-induced analgesia in the rat tail-flick test. In addition, the integrity of the dorsal APtN is necessary for the analgesic effect of 2 but not 100 Hz EA.