Inhibition Of Nociception Research Articles

Pain Catastrophizing is Not Associated With Spinal Nociceptive Processing in People With Chronic Widespread Pain.

Objectives:Pain catastrophizing has been associated with higher pain intensity, increased risk of developing chronic pain and poorer outcomes after treatment. Despite this, the mechanisms by which pain catastrophizing influences pain remain poorly understood. It has been hypothesized that pain catastrophizing may impair descending inhibition of spinal level nociception. The aims of this study were to compare spinal nociceptive processing in people with chronic widespread pain and pain-free controls and examine potential relationships between measures of pain catastrophizing and spinal nociception.Materials and Methods:Twenty-six patients with chronic widespread pain and 22 pain-free individuals participated in this study. Spinal nociception was measured using the nociceptive flexion reflex (NFR) threshold and NFR inhibition, measured as the change in NFR area during exposure to a second, painful conditioning stimulus (cold water immersion). Pain catastrophizing was assessed using the Pain Catastrophizing Scale and a situational pain catastrophizing scale.Results:Compared with pain-free controls, patients with chronic widespread pain had higher pain catastrophizing scores and lower NFR thresholds. Although NFR area was reduced by a painful conditioning stimulus in controls, this was not apparent in individuals with chronic widespread pain. No significant correlations were observed between measures of pain catastrophizing and spinal nociception.Discussion:Despite increased excitability and decreased inhibition of spinal nociception in patients with chronic widespread pain, we could find no evidence of a significant relationship between pain catastrophizing and measures of spinal nociceptive processing.

P247 Painful laser evoked potential inhibition during high-frequency non-noxious somatosensory stimulation

Objectives The inhibition of single nociceptive inputs by single non-painful stimuli was shown to occur at supraspinal level (Testani et al., 2015). However, the neurophysiological mechanism subserving the analgesia induced by rubbing the painful part of the body or during TENS is still unknown. Our aim was to investigate the site of this inhibition. Methods We studied 10 healthy volunteers. LEPs were recorded after stimulation of the radial and ulnar territories of both the right and left hand dorsum in 2 conditions: (1) no conditioning stimulation (baseline condition), and (2) high-frequency (5 Hz) non-painful electrical stimulation of the right radial nerve (gating condition). Results As compared to the baseline, in the gating condition the N2/P2 amplitude was reduced in amplitude after stimulation of the radial territory of both hands ( p 0.001 and p 0.001 for right and left hand, respectively) and of the right ulnar region (p = 0.008), while no inhibition was found to left ulnar region stimulation (p = 0.06). Discussion Our results show that high-frequency non-painful stimulation of the right radial nerve inhibits the nociceptive input coming from both the ispilateral and contralateral homotopic regions, and from a close ispilateral heterotopic territory. On the contrary, it does not have any effect on the nociceptive input due to stimulation of a contralateral heterotopic area. Conclusion Spinal segmental mechanisms are mainly involved in the nociceptive input inhibition by high-frequency non-noxious somatosensory stimulation. Significance Pain inhibition induced by high-frequency somatosensory stimulation, such as TENS, is likely to occur at the spinal cord level.

Effect of Polymers on the Physicochemical Properties and Biological Performance of Fenoprofen Calcium Dihydrate-Triacetyl-β-Cyclodextrin Complex.

Background: Fenoprofen calcium dehydrate (FCD) is counted as a non-steroidal, anti-inflammatory, anti-arthritic drug. FCD is slightly water soluble. It is indicated for mild pain relief, where the suggested dosage is 200 mg orally every 4 to 6 h. Aim: Reduce dissolution efficiency, reach an extended therapeutic effect and reduce the frequency of the drug side effects. Method: Combination of the co-evaporated drug:triacetyl-β-cyclodextrin complex prepared in a ratio of 1:3 and either of two polymers—hydroxylpropylmethyl cellulose (HPMC) or ethyl cellulose (EC)—in the same formulation. In vitro dissolution studies were carried in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, by using the USP dissolution tester (rotating paddle apparatus). The FCD in vitro release from EC/drug complex was markedly retarded. Interaction between fenoprofen, TA-β-CD, EC, HPMC in the solid state were confirmed by FT-IR, DSC, XRD and SEM. In vivo studies assessed the anti-inflammatory and analgesic activities and the results were compared with the market product Nalfosab® Capsules. Results: Remarkable inhibition of inflammation and nociception after 24 h was attained for EC/drug complex. Conclusions: EC/drug complex has a sustained effect due to high remaining amount after elapsing with remarkable inhibition of inflammation.

Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray.

The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception.

THE 2α-3β-6β-23-TETRAHYDRO-OLEAN-12-EN-28-OIC ACID FROM THE LEAVES OF CHRYSOBALANUS ICACO L. ATTENUATES THE INFLAMMATORY HYPERNOCICEPTION IN MICE

Objective: The species Chrysobalanus icaco L., popularly known as abajurú, abajeru, has frequently been associated with antiangiogenic, anti-inflammatory and antirheumatic effects. The 2α-3β-6β-23-tetrahydro-olean-12-en-28-oic acid (THOA) was isolated from the methanolic extract of Chrysobalanus icaco leaves. Thus, the aim of the study was to evaluate the antinociceptive and anti-inflammatory activities of THOA.Methods: Acetic acid-induced abdominal writhing, formalin, von frey and open field tests were performed in mice. The number of writhes, licking time, mechanical threshold and walked squares by animals were the evaluation parameters applied, respectively. In addition, quantification of IL-1β and TNF-α were also performed. The THOA was administered orally at doses of 1–10 mg/kg in male mice. In addition, water, vehicle, morphine (5.01 mg/kg), acetylsalicylic acid (100 mg/kg), and dexamethasone (2.25 mg/kg) were administered.Results: The THOA showed effect with 5 and 10 mg/kg in the acute pain induced by acetic acid (49% and 62% contortion inhibition), carrageenan (150% and 188% increase in mechanical threshold) and formalin (36% and 60% licking inhibition), respectively. These results indicate an inhibition of hyper nociception, while the reduction in the production of cytokines (TNF-α inhibition–64% and 88%; IL-1β inhibition–48% and 55%, respectively) confirmed the inflammatory inhibition by carrageenan. The THOA did not induce motor impairment. The THOA was not toxic after oral administration (LD50>50 mg/kg).Conclusion: These data provide initial evidence that THOA decreases the inflammatory hyper nociception probably by inhibition of IL-1β and TNF-α production, proving to be effective in reducing pain and inflammation.

Artificial Anion Conducting Channelrhodopsins with Tuned Spectra, Modified Kinetics and Enhanced Light Sensitivity

Prior to the discovery of natural anion conducting channelrhodopsins (nACRs), artificial anion conducting channelrhodopsins (aACRs) have been developed, improved and were successfully applied in vivo. We asked whether the approaches used to create aACRs can be transferred to other well-characterized cation-conducting channelrhodopsins to obtain aACRs with a broader variation of biophysical properties. The screen of 18 different constructs yielded two new aACRs, termed Phobos and Aurora, which express well in neurons and provide sufficient photocurrents for efficient silencing. They can be activated with far blue or far red light, respectively, making them suitable for combination with other spectrally distinct actuators or sensors of the optogenetic toolbox. Furthermore, introduction of step function mutations slowed down the photocycle of the new aACRs up to 10000-fold, thus greatly enhancing light sensitivity. These light-switchable versions of Phobos and Aurora can further be reversibly toggled between open and closed states with brief light pulses of different wavelengths. Both variants and their step function mutants showed perfect selectivity for chloride ions and where tested in hippocampal slice cultures, reliably inhibiting action potential firing. In drosophila larvae, the new aACR variants showed robust and specific light-dependent in vivo inhibition of locomotion and nociception. Ongoing experiments will reveal in vivo aACR functionality in rodents and adult drosophila.

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

BackgroundTolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.MethodsThe microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.ResultsWe found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.ConclusionsMetformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0754-9) contains supplementary material, which is available to authorized users.

Analgesia/nociception monitoring for opioid guidance: meta-analysis of randomized clinical trials.

The adequate suppression of nociception is, besides induction of unconsciousness and immobility, the main objective during anesthesia. Analgesics, most commonly opioids, are usually titrated by established clinical surrogates of nociception. Recently, monitoring techniques became available to evaluate analgesia/nociception during anesthesia and provide better measures then clinical evaluation alone. They are primarily derived from autonomic response on physiologic standard measures. A literature search and systematic review of randomized controlled trials was performed. Trials enrolling patients undergoing general anesthesia and comparing the effects of opioids guided by analgesia/nociception monitoring were considered. Studies were analyzed regarding the outcome effects of opioid therapy, intraoperative events and postoperative pain. Meta-analyses were performed for each outcome separately using a fixed-effects model and random effects models. Seven applicable randomized clinical trials using three different methods for analgesia/nociception monitoring and opioid guidance during anesthesia were found. All but one trial were single centre studies, with a high heterogeneity between the trials and differences in predefined primary outcome. This meta-analysis found that the use of analgesia/nociception monitoring was associated with a significant reduction of movement events, a non-significant trend towards reduction of intraoperative administered opioids and emergence time, but was inconclusive with regard to effects on hemodynamic events, postoperatively reported pain and opioid consumption. Monitoring analgesia/nociception is often reliant on regular physiologic conditions, like sinus rhythm. Opioid guidance dependent on analgesia/nociception monitoring during anesthesia may have beneficial and clinically relevant effects, however the number of currently available randomized controlled studies is low and conclusions are hampered by heterogeneity. More studies with focussed clinical endpoints are therefore needed.

Is blood glucose associated with descending modulation of spinal nociception as measured by the nociceptive flexion reflex?

ObjectivesPrior research has shown a relationship between blood glucose levels and some forms of self-regulation (eg, executive function), with low blood glucose levels associated with impaired self-regulation. Further, engagement in self-regulation tasks depletes blood glucose. Given these relationships, the present study examined whether blood glucose is associated with another form of self-regulation, ie, descending pain modulatory processes.MethodsForty-seven (32 female) pain-free participants were recruited and completed testing. Blood glucose was measured from finger sticks and a digital meter before and after experimental pain tests. Pain tests included the nociceptive flexion reflex (NFR) threshold to assess descending modulation of spinal nociception, but also electric pain threshold to assess perceptual pain detection. The Stroop color word naming test was also assessed before and after pain testing to examine changes in executive function.ResultsResults indicated that mean blood glucose levels decreased after pain testing, but Stroop performance did not significantly change. Importantly, changes in blood glucose were correlated with NFR threshold, such that decreases in blood glucose were associated with lower NFR thresholds (reduced descending inhibition). Changes in blood glucose were unrelated to pain threshold or executive function.ConclusionThis study suggests that glucose depletion may impair performance of descending inhibitory processes, without impacting the perceptual detection of pain (pain threshold). Although findings need to be replicated, maintaining adequate glucose levels may be necessary to support inhibition of spinal nociception.

Progress in pain management to improve small ruminant farm welfare

Pain management to improve the welfare of livestock during aversive husbandry interventions is increasingly expected of global farming systems, although few products are available for use by farmers to achieve this. An exception is the ‘spray-on’ topical anaesthetic (TS) formulation containing lignocaine and bupivicaine (Tri-Solfen®; Bayer Animal Health, Pymble, NSW, Australia) originally developed for the mulesing operation in sheep in Australia, where breech skin is removed to create a ‘bare area' that significantly decreases the risk of myiasis from Lucilia cuprina. Over 40 million Merino lambs have now received pain management and some flocks have continued mulesing to manage life-time risk of blowfly strike until ‘wrinkle’ phenotypes are removed through genetic improvements. This innovation enabled investigations of TS spray for pain from other procedures in lambs and kids (and calves), including surgical castration, tail-docking, disbudding, ear-tagging and shearing wounds. Our observations suggest that practical pain management during surgical interventions should commence with inhibition of nociception and that TS is far more efficacious than previously considered. For multi-modal pain management, ameliorating wound sensitisation by the use of nonsteroidal anti-inflammatory drugs (NSAID’s) is increasingly available and may also have a role, particularly when cautery is used (eg tail docking and disbudding). Further modification of pain through centrally-acting drugs altering physiology and cognition, such as low dose xylazine, is also possible but requires closer veterinary supervision than is available in most extensive farming systems. We note that Tri-Solfen® use by farmers has improved welfare attitudes on many farms and the approach has potential application for global livestock industries.

Endogenous inhibition of pain and spinal nociception in women with premenstrual dysphoric disorder.

PurposePremenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle.MethodsParticipants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM.ResultsCompared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR.ConclusionEndogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase.

Efficacy of Preemptive oral pregabalin for prolonging post-operative analgesia in modified radical mastectomies

Background: The concept of preemptive analgesia had evolved in the recent years. Present days multimodal approach is the most preferred practice for perioperative pain relief, as no single agent is effective in inhibition of nociception without its side effects. Pregabalin originally a spasmolytic, now used as a newer anti-epileptic drug, in the management of generalized and partial epileptic seizures. Its use as a preemptive analgesic in many surgical procedures had proved promising results. Hence the aim of our study was to evaluate efficacy of preemptive pregabalin for prolonging post-operative analgesia, reducing post-operative opioid analgesic requirement and haemodynamic stability. Material and Methods: 80 patients of ASA grade I and II physical status posted for elective modified radical mastectomy were divided into 2 groups of 40 each. Group T –received pregabalin 150 mg orally 1 hour before general anaesthesia. Group C – received identical empty capsules as placebo 1 hour before general anaesthesia. Results: The postoperative VAS scores were significantly lower and duration of analgesia was longer in pregabalin group as to control group. The total analgesic consumption, PONV scores were also lower in pregabalin group. Ramsay sedation scores were slightly higher in pregabalin group but were acceptable clinically. The side effects were similar in both groups. Conclusion: Preemptive 150mg oral pregabalin reduces post-operative pain scores(VAS)significantly, provides longer duration and better quality of post-operative analgesia, reduces opioid analgesic requirement and attenuates haemodynamic response to laryngoscopy, endotracheal intubation and also extubation without increase the side effects when used in optimal doses. Keywords: Preemptive analgesia, Pregabalin, VAS scores, Hemodynamic stability, Modified radical mastectomies

Descending nociceptive inhibition is modulated in a time-dependent manner in a double-hit model of chronic/tonic pain

Clinical evidences suggest that an imbalance between descending inhibition and facilitation drives the development of chronic pain. However, potential mechanisms promoting the establishment of a persistent pain state and the increased pain vulnerability remain unknown. This preclinical study was designed to evaluate temporal changes in descending pain modulation at specific experimental endpoints (12, 28, 90 and 168days) using a novel double-hit model of chronic/tonic pain (first hit: chronic constriction injury (CCI) model; second hit: tonic formalin pain in the contralateral hindpaw). Basal activity of bulbo-spinal monoaminergic systems was further assessed through liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) screening of cerebrospinal fluid (CSF). We found that CCI-operated rats exhibited a reduced nociceptive response profile, peaking on day 28, when subjected to tonic pain. This behavioral response was accompanied by a rapid increase in basal CSF serotonin and norepinephrine levels 12days after neuropathy, followed by a return to sham levels on day 28. These molecular and behavioral adaptive changes in descending pain inhibition seemed to slowly fade over time. We therefore suggest that chronic neuropathic pain produces a transient hyperactivation of bulbo-spinal monoaminergic drive when previously primed using a tonic pain paradigm (i.e., formalin test), translating into inhibition of subsequent nociceptive behaviors. Altogether, we propose that early hyperactivation of descending pain inhibitory mechanisms, and its potential ensuing exhaustion, could be part of the temporal neurophysiological chain of events favoring chronic neuropathic pain establishment.

Activation of Adenosine Monophosphate-activated Protein Kinase Suppresses Neuroinflammation and Ameliorates Bone Cancer Pain: Involvement of Inhibition on Mitogen-activated Protein Kinase.

Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain. The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects. Resveratrol and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 ± 0.56 vs. 4.1 ± 0.37; 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 ± 0.17 vs. 4.1 ± 0.37, mean ± SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 ± 1.35 vs. 10.1 ± 0.56, mean ± SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors-mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol. AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.

(107) Pain resilience is positively correlated with nociceptive flexion reflex threshold

The Pain Resilience Scale (PRS) has recently been developed as a pain-specific measure of dispositional resilience, or the ability to maintain positive physical and emotional functioning despite pain. The PRS is a 14-item scale that examines an individual’s reported propensity to exhibit resilient responses to prolonged or intense pain. Exploratory and Confirmatory Factor analyses have identified two subscales of the PRS, labeled “Stay Positive” and “Carry On”, which examine cognitive-affective and behavioral-motivational resilience, respectively. Although measures of general (i.e. trait) resilience have previously been related to acute pain experience, the relationship between responses on a pain-specific resilience measure and acute pain perception has not been examined. Accordingly, the current study examined the relationship between pain resilience, as measured by the Pain Resilience Scale, and the Nociceptive Flexion Reflex (NFR) threshold in men and women with and without subclinical pain (n=27). NFR is a polysynaptic withdrawal reflex of the biceps femoris that can be activated by electrical stimulation of the sural nerve. Participants completed measures of pain resilience, pain catastrophizing, and pain-related fear prior to their NFR threshold assessment. NFR threshold was assessed using an up-down staircase method, wherein stimulus intensity was increased until a reflex was detected and then decreased until the reflex disappeared. This procedure was repeated three times to establish a reliable reflex threshold. Results of correlational analyses indicated that the PRS was positively related to NFR threshold (r=0.49, p< .01), whereas pain catastrophizing and pain-related fear were not related to NFR. These findings provide preliminary validation of the PRS in the context of acute experimental pain. Furthermore, the present findings are consistent with existing evidence of no relationship between pain vulnerability (e.g., catastrophizing, anxiety sensitivity) and spinal nociception, and provide novel evidence that pain resilience may be associated with greater descending inhibition of spinal nociception.

Study of Antinociceptive Activity of Kaempferia galanga from Bangladesh in Swiss albino Mice

Kaempferia galanga (K. galanga) (Family: Zingiberaceae) has been used in the folk medicine for the treatment of inflammation, chest pain, cholera, headache, toothache, hypertension, and abdominal pain. Previous investigations on this plant suggested that the methanol extract of rhizome showed the analgesic activity. Therefore, the present study investigated the antinociceptive activity of different extracts of rhizome and leaves of K. galanga. The antinociceptive activity was evaluated by using acetic acid-induced writhing, hot plate and tail immersion tests in Swiss albino mice at the doses of 100 and 200 mg/kg body weight p.o. The acetone extract of rhizome (ACR), as well as petroether fraction (PEF), chloroform fraction (CHF), methanol fraction (MEF) and acetone extract of leaves (ACL) were examined for antinociceptive activity. In this study, all the extracts displayed significant (p<0.05 and p<0.001) antinociceptive action in a dose dependent manner. In acetic acid induced writhing method, chloroform and methanol extract of rhizome (200 mg/kg) showed 81.22% and 70.12% writhing inhibition, respectively whereas the standard drug Diclofenac-sodium (25 mg/kg) and Aspirin (100 mg/kg) exhibited 80.72% and 61.94% inhibition. In hot plate and tail immersion tests, the petroether extract of rhizome and acetone extract of leaves (200 mg/kg) produced maximum 69.41% and 81.69% nociception inhibition of thermal stimulus respectively. In this study Morphine (5 mg/kg) was used as standard. The present study revealed that the acetone extracts and fractions of rhizome and leaves of K. galanga possess an antinociceptive property which supports its use in traditional medicine and suggesting that the plant may be further investigated to discover its pharmacologically active natural products.

Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states.

Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.

Effects of simulated weightlessness on intramuscular hypertonic saline induced muscle nociception and spinal Fos expression in rats

We assessed the effects of simulated weightlessness, hindlimb unloading (HU) by 7 days of tail suspension, on noxious mechanically and heat evoked spinal withdrawal reflexes and spinal Fos expression during muscle nociception elicited by intramuscular (i.m.) injection of hypertonic (HT; 5.8%) saline into gastrocnemius muscle in rats. In HU rats, i.m. HT saline-induced secondary mechanical hyperalgesia was enhanced, and secondary heat hypoalgesia was significantly delayed. After 7 days of HU, basal Fos expression in spinal L4-6 segments was bilaterally enhanced only in superficial (I–II) but not middle and deep laminae (III–VI) of the spinal dorsal horn, which finding was not influenced by tail denervation. Unilateral i.m. HT saline injection increased spinal Fos expression bilaterally in both the control rats and 7 days of HU rats. The HT saline-induced bilateral increase of spinal Fos occurred within 0.5h and reached its peak within 1h, after which it gradually returned to the control levels within 8h. Spatial patterns of spinal Fos expression differed between the control group and 7 days of HU group. In superficial laminae, the HT saline-induced increases in Fos expression were higher and in the middle and deep laminae V–VI lower in the 7 days of HU than control rats. It is suggested that supraspinal mechanisms presumably underlie the effects of HU on spinally-organized nociception. Simulated weightlessness may enhance descending facilitation and weaken descending inhibition of nociception.

Orexin A induced antinociception in the ventral tegmental area involves D1 and D2 receptors in the nucleus accumbens

Previous studies have shown that there are functional interactions among the lateral hypothalamus (LH), ventral tegmental area (VTA) and the nucleus accumbens (NAc), implicating pain modulation in the central nervous system. It has been shown that the LH–VTA orexinergic projecting neurons play an important role in mediating the suppression of nociception in animal models. However, little is known about the function of intra-VTA orexin receptors and involvement of D1/D2 receptors within the NAc in this antinociception. In the present study, we investigated the effect of direct administration of orexin A into the VTA, and examined the role of intra-accumbal dopamine receptors in tail-flick test as a model of acute nociceptive responses in rats. Adult male Wistar rats were unilaterally implanted by two separate cannulae into the VTA and NAc. The results showed that intra-VTA orexin A (0.055, 0.55, 5.5 and 55ng/0.3μl saline) could induce antinociception in a dose-dependent manner. In two separated supergroups, rats received intra-accumbal infusions of D1 and D2 receptor antagonists, SCH-23390 and sulpiride (0.125, 0.25, 1 and 4μg/rat) prior to intra-VTA orexin A (5.5ng/rat) administration respectively. Antinociceptive responses of drugs are represented as maximal possible effect in 5, 15, 30, 45 and 60min after their administrations. Our findings showed that intra-accumbal SCH-23390 and sulpiride dose-dependently prevented intra-VTA orexin-induced antinociception. Nevertheless, this effect is more potent in animals that received D2 receptor antagonist. It is supposed that orexin A can induce the antinociception through activation of orexinergic receptors which activate the dopaminergic inputs to the NAc in rats.

The role of sodium channels in painful diabetic and idiopathic neuropathy.

Painful neuropathies are frequently encountered in clinical practice as an early or late complication of several systemic disorders. Among them, diabetes is one of the most important due to its epidemiology and the relevance for regulatory agencies in the assessment of efficacy of new analgesics. However, the presentation and course of painful neuropathies, as well as the response to available drugs, are highly variable and unpredictable, posing significant challenges in the management of patients. Experimental and clinical studies have suggested that polymorphisms and mutations in pain-related genes are involved in the facilitation or inhibition of nociception, and might modulate neuropathic pain and the response to analgesics in patients. Voltage-gated sodium channel genes are among the most relevant, due to the key role of these membrane proteins in the physiology of nociception and their involvement in the pathogenesis of idiopathic painful small fiber neuropathies. These compelling features make sodium channel candidate targets for a novel approach to painful diabetic and idiopathic neuropathies, which will hopefully allow a new classification of patients and more effective targeted treatments.