Analgesic Effects In Animal Models Research Articles

Analgesic effects of ich phu dan capsules in experimental animals

Ich phu dan capsules are intended to treat menstrual pain. The study aimed to assess the analgesic effects of Ich phu dan capsules in animal models. Three animal models were used: a hot plate, tail flick and acetic acid-induced writhing test. Mice were divided into four groups and were given orally: group 1 distilled water; group 2 control drug (codeine phosphate in hot plate and tail flick tests or aspirin in writhing test); groups 3 and 4: Ich phu dan at the doses of 1.44 capsules (approx 521.1 mg dried extract) or 2.88 capsules (approx 1042.2 mg dried extract)/kg b.w/day, respectively. The results showed that Ich phu dan capsules at both doses increased the mice’s reaction time in hot plate and tail flick models and decreased the number of acetic acid-induced writhing movements in mice. There was no statistically significant difference between the two doses of Ich phu dan capsules. In conclusions, Ich phu dan capsules at the doses of 1.44 capsules (approx 521.1 mg dried extract) and 2.88 capsules (approx 1042.2 mg dried extract)/kg b.w/day showed significant analgesic effect in animal models.

Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na+/Ca2+ Exchanger Inhibitor

KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of reverse sodium-calcium exchanger (NCX). It has been shown to have neuroprotective and analgesic effects in animal models; however, the detailed molecular mechanisms remain elusive. In the current study, we investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders, using the whole-cell patch clamp techniques. Our data show that KB-R7943 irreversibly inhibits homomeric ASIC1a channels heterologously expressed in Chinese Hamster Ovary (CHO) cells in a use- and concentration-dependent manner. It also reversibly inhibits homomeric ASIC2a and ASIC3 channels in CHO cells. Both the transient and sustained current components of ASIC3 are inhibited. Furthermore, KB-R7943 inhibits ASICs in primary cultured peripheral and central neurons. It inhibits the ASIC-like currents in mouse dorsal root ganglion (DRG) neurons and the ASIC1a-like currents in mouse cortical neurons. The inhibition of the ASIC1a-like current is use-dependent and unrelated to its effect on NCX since neither of the other two well-characterized NCX inhibitors, including SEA0400 and SN-6, shows an effect on ASIC. Our data also suggest that the isothiourea group, which is lacking in other structurally related analogs that do not affect ASIC1a-like current, may serve as a critical functional group. In summary, we characterize KB-R7943 as a new ASIC inhibitor. It provides a novel pharmacological tool for the investigation of the functions of ASICs and could serve as a lead compound for developing small-molecule drugs for treating ASIC-related disorders.

Preemptive Levetiracetam Decreases Postoperative Pain: A Double-Blind, Randomised, Control Trial.

Background Previously many studies have found the use of anti-epileptic drugs such as pregabalin, carbamazepine, and gabapentin in pain management. In addition, levetiracetam (LEV), an effective anti-epileptic drug, has shown analgesic effects in animal models. We aimed to evaluate the effect of oral LEV as pre-emptive analgesia in patients who underwent laparoscopic cholecystectomy under general anaesthesia and postoperative fentanyl requirements. Material and methods Forty-two patients of the American Society of Anaesthesiologists (ASA) grade I and II of either gender posted for elective laparoscopic cholecystectomy surgery were included in this double-blind, randomised, placebo-controlled study. Patients were divided into two equal groups of 21 each to receive either tablet LEV 500 mg or a matching placebo tablet, given 1 hour before surgery. Postoperative pain was assessed by a visual analogue scale (0-100 mm), where 0 meant no pain and 100, worst pain. In addition, patients received IV fentanyl as rescue analgesia during the first 24 hours of the postoperative period. Results Nineteen patients in the LEV group and 20 in the placebo group completed the study. Patients in the LEV group had significantly lower pain scores at all time intervals except 0 hours and reduced fentanyl consumption postoperatively in the first 24 hours (p<0.05). Side effects were comparable in both groups. Conclusion A single, preoperative dose of oral LEV 500 mg significantly decreases post-surgical pain and fentanyl demand as rescue analgesia in elective laparoscopic cholecystectomy.

Analgesic activity of Phong Thap Dan tablets in animal models

Phong thap dan tablets are intended to treat low back pain. This study was carried out to evaluate theanalgesic effects of Phong thap dan tablets in experimental animals. The analgesic effects were evaluated inthree animal models: hot plate, mechanical stimulation and acetic acid-induced writhing test. Mice were dividedinto 4 groups given oral water, control drug (codein phosphate in hot plate and mechanical stimulation tests oraspirin in writhing test), Phong thap dan at 2.88 tablets (1.44 g) or 8.64 tablets (4.32 g)/kg b.w/day, respectively.Our results showed that Phong thap dan tablets at both doses increased the reaction time to thermal stimulation,increased the paw withdrawal latency and the force required to elicit a paw withdrawal and decreased thenumber of acetic acid-induced writhing movements in mice. There was no statistically significant differencebetween 2 doses of Phong thap dan tablets in three animal models. We conclude that Phong thap dan tabletsat the doses of 2.88 tablets and 8.64 tablets/kg b.w/day showed significant analgesic effect in animal models.

Distinct synaptic mechanisms underlying the analgesic effects of γ-aminobutyric acid transporter subtypes 1 and 3 inhibitors in the spinal dorsal horn.

Normalization of the excitatory and inhibitory balance by increasing the levels of endogenous inhibitory neurotransmitters by blocking their reuptake is a promising therapeutic strategy for relieving chronic pain. Pharmacological blockade of spinal γ-aminobutyric acid (GABA) transporter subtypes 1 and 3 (GAT1 and GAT3) has been reported to generate analgesic effects in animal models of neuropathic pain. Here, we explored the synaptic mechanisms underlying their analgesic effects in the spinal dorsal horn. Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult mice, and the effects of GAT inhibitors on miniature and evoked postsynaptic currents were examined. Behaviorally, GAT inhibitors were intrathecally applied to assess their effects on mechanical hypersensitivity in mice developing neuropathic pain after partial sciatic nerve ligation. The GAT1 inhibitor NNC-711 reduced the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of C-fiber-mediated EPSCs, and the GAT3 inhibitor SNAP-5114 reduced the amplitude of A-fiber-mediated and C-fiber-mediated EPSCs. These effects were antagonized by the GABAB receptor antagonist CGP55845. Consistently, the analgesic effect of intrathecally injected NNC-711 and SNAP-5114 in mice developing mechanical hypersensitivity after partial sciatic nerve ligation was abolished by CGP55845. Thus, GAT1 and GAT3 inhibitors exert distinct GABAB receptor-mediated inhibitory effects on excitatory synaptic transmission in the spinal dorsal horn, which most likely contributes to their analgesic effects.

Mechanistic Rationale and Clinical Efficacy of Hyperbaric Oxygen Therapy in Chronic Neuropathic Pain: An Evidence-Based Narrative Review.

Background Chronic neuropathic pain is a condition affecting an increasing proportion of the general population and its management requires a comprehensive, multidisciplinary program. A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in several chronic neuropathic pain conditions; however, its role and efficacy remain unclear. Purpose To summarize current evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy. Methods This narrative review was conducted after searching the following databases (Medline, Embase, Cochrane, PsycINFO, the Web of Science, Scopus, ClinicalTrials. gov, WHO ICTRP, and ProQuest Digital Dissertation) from January 1946 to March 2020. Articles published in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention were included. Results A total of 2971 citations were identified. A total of 29 studies were included in this review. The mechanisms of action for HBOT use in neuropathic conditions included the primary effects of hyperoxia and edema resolution, as well as the secondary effects pertinent to the production of oxygen and nitrogen reactive species (serving as pain signaling molecules), nitric oxide-dependent release of opioid peptides, and reduction of inflammatory mediators. A robust evidence for HBOT use in the clinical setting was associated with chronic regional pain syndrome and chronic primary bladder pain syndrome. Some evidence supported its use for chronic secondary (peripheral) neuropathic pain including radiation-induced plexus neuropathies, postherpetic neuralgia, and trigeminal neuralgia. Conclusions HBOT has been shown to have antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. Human studies demonstrated beneficial effects of HBOT in improving clinical outcomes such as pain scores, pain-related symptoms, and quality of life. A systematic methodology of HBOT application is necessary to confirm its safety and efficacy.

Analgesic effect of dl-THP on inflammatory pain mediated by suppressing spinal TRPV1 and P2X3 receptors in rats.

Tetrahydropalmatine (dl-THP) demonstrates an analgesic effect in animal models of neuropathic and inflammatory pain, however, the underlying mechanisms of its pharmacological action within the spinal cord remains unclear. Both P2X3 receptor and TRPV1 are associated with the development and progression of such neuropathic and inflammatory pain. Here, we found that both pre-treatment and post-treatment with dl-THP could attenuate Bee Venom (BV)-induced persistent spontaneous pain-related behaviors in rats. Further, the dl-THP also exerted both preventive and therapeutic analgesic effects in BV-induced primary thermal and mechanical pain hypersensitivity as well as in mirror-image thermal pain hypersensitivity. The Rota-Rod treadmill test revealed that the dl-THP administration did not alter the rats' motor coordinating performance. The TRPV1 and P2X3 receptor proteins increased markedly in the spinal cord of the rats following s.c. BV injection, which was significantly suppressed by dl-THP. These results suggest that dl-THP exerts a robust antihyperalgesia effect through down-regulation of P2X3 receptors and TRPV1 in inflammatory pain, providing a scientific basis for the translation of dl-THP treatment in clinics.

Anti-inflammatory and analgesic activities of &lt;i&gt;Clerodendrum capitatum&lt;/i&gt; (Willd) Schum. &amp; Thonn. (Verbenaceae) leaves

Clerodendrum capitatum (Willd) Schumach and Thonn. (Verbenaceae) is a perennial herb, which grows up to 0.5 m to 2 m high. It is widespread over North-East, East, and South Central Africa. It is known as “bambaro or maashayi” by the Hausas of Northern Nigeria. The leaves are used traditionally to treat intercostal pain, headaches and toothaches. The aim of this study is to evaluate the anti-inflammatory and analgesic activities of the aqueous ethanol extract and fractions of C. capitatum. The anti-inflammatory activity was investigated using carrageenan induced rat paw oedema model, while acetic acid induced mice writhing model was used to evaluate the anti-nociceptive property. The oral median lethal dose values were found to be greater than 5,000 mg/kg for the aqueous ethanol extract, ethyl acetate and n-butanol fractions, while that of dichloromethane fraction was less than 2000 mg/kg using OECD method. The acetic acid induced writhing was significantly (P&lt;0.05-0.001) reduced particularly for the EF and NF fractions at 200 mg/kg (93.12% and 98.79%). DF showed percentage inhibition of 87.59% and 81.75% at 50 and 100 mg/kg respectively. The extracts and fractions also caused a significant (P&lt;0.05-0.001) dose dependent reduction of inflammation induced by carrageenan when compared with the negative control with the maximum inhibitory effect of 43.69% observed in Ethyl acetate fraction at 50 mg/kg dose at the 3rd hour. It can be concluded that the leaf extracts of C. capitatum possess anti-inflammatory and analgesic effects in animal models, which may be mediated through the phytochemical constituents present in the extract and fractions of the plant.&#x0D; Keywords: Clerodendrum capitatum; Anti-inflammatory; Analgesic; OECD

Antinociceptive effect of intrathecal injection of miR-9-5p modified mouse bone marrow mesenchymal stem cells on a mouse model of bone cancer pain

BackgroundA growing body of studies have indicated that bone marrow mesenchymal stem cells (BMSCs) have powerful analgesic effects in animal models of bone cancer pain. Here, we explored the molecular mechanisms underlying how BMSCs alleviate pain sensation in a mouse model of bone cancer pain.MethodsC3H/HeN adult male mice were used to generate a bone cancer pain model. BMSCs were isolated from mouse bone marrow, modified by transfection with microRNA-9-5p (miR-9-5p), and infused into the spinal cord. Spontaneous flinches, paw withdrawal latency, limb-use score, and weight-bearing score were used to assess pain-related behaviors. ELISA, RT-PCR, western blot, and luciferase assay were used to assess gene expressions.ResultsOur results show that miR-9-5p regulated the expression of both repressor element silencing transcription factor (REST) and μ-opioid receptors (MOR) by targeting REST in primary mouse BMSCs. Overexpression of miR-9-5p reversed the activation of inflammatory pathway in TNF-α- and IL-6-treated BMSCs. In addition, miR-9-5p modified BMSCs alleviated cancer pain in the sarcoma-inoculated mouse model. MiR-9-5p modified BMSCs suppressed cytokine expression in the spinal cord of sarcoma-inoculated mice by suppressing REST gene expression.ConclusionsOur results indicate that miR-9-5p modified BMSCs can relieve bone cancer pain via modulating neuroinflammation in the central nervous system, suggesting genetically modified BMSCs could be a promising cell therapy in pain management.

Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats.

URB937, a peripheral fatty acid amide hydrolase (FAAH) inhibitor, exerts profound analgesic effects in animal models. We examined, in rats, (1) the pharmacokinetic profile of oral URB937; (2) the compound's ability to elevate levels of the representative FAAH substrate, oleoylethanolamide (OEA); and (3) the compound's tolerability after oral administration. We developed a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method to measure URB937 and used a pre-existing LC/MS-MS assay to quantify OEA. FAAH activity was measured using a radioactive substrate. The tolerability of single or repeated (once daily for 2weeks) oral administration of supramaximal doses of URB937 (100, 300, 1000mg/kg) was assessed by monitoring food intake, water intake and body weight, followed by post-mortem evaluation of organ structure. URB937 was orally available in male rats (F=36%), but remained undetectable in brain when administered at doses that maximally inhibit FAAH activity and elevate OEA in plasma and liver. Acute and subchronic treatment with high doses of URB937 was well-tolerated and resulted in FAAH inhibition in brain. Pain remains a major unmet medical need. The favourable pharmacokinetic and pharmacodynamic properties of URB937, along with its tolerability, encourage further development studies on this compound.

Spinal α2 -adrenoceptors and neuropathic pain modulation; therapeutic target.

Neuropathic pain can arise from disease or damage to the nervous system. The most common symptoms of neuropathic pain include spontaneous pain, allodynia, and hyperalgesia. There is still limited knowledge about the factors that initiate and maintain neuropathic pain. However, ample evidence has proved the antinociceptive role of spinal α-adrenoceptors following nerve injury. It is well-documented that noradrenergic descending pathways from supraspinal loci exert an inhibitory influence on the spinal cord nociceptive neurons, mostly through the activation of spinal α2 -adrenoceptors. This, in turn, suppresses transmission of pain input and the hyperexcitability of spinal dorsal horn neurons. There is considerable evidence demonstrating that spinal application of α2 -adrenoceptor agonists leads to analgesic effects in animal models of neuropathic pain. Today, despite the recent rapid development of neuroscience and drug discovery, effective drugs with clear basic mechanisms have remained a mystery. Here, we give an overview of the cellular mechanisms through which brainstem adrenergic descending inhibitory processing can alter spinal pain transmission to the higher centres, and how these pathways change in neuropathic pain conditions focusing on the role of spinal α2 -adrenoceptors in the spinal dorsal horn. We then suggest that α2 -adrenoceptor agonist may be useful to treat neuropathic pain. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

NMDA Receptor Dependent Long-term Potentiation in Chronic Pain

Since the discovery of NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in the hippocampus, many studies have demonstrated that NMDAR dependent LTP exists throughout central synapses, including those involved in sensory transmission and perception. NMDAR LTP has been reported in spinal cord dorsal horn synapses, anterior cingulate cortex and insular cortex. Behavioral, genetic and pharmacological studies show that inhibiting or reducing NMDAR LTP produced analgesic effects in animal models of chronic pain. Investigation of signalling mechanisms for NMDAR LTP may provide novel targets for future treatment of chronic pain.

Alkylsulfanyl analogs as potent α2δ ligands

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.

Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans

Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta −0.41; 95% CI-0.69, −0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels.

Neuroinflammation, Bone Marrow Stem Cells, and Chronic Pain.

Current treatments for chronic pain, such as inflammatory pain, neuropathic pain, and cancer pain are insufficient and cause severe side effects. Mounting evidence suggests that neuroinflammation in the peripheral and central nervous system (PNS and CNS) plays a pivotal role in the genesis and maintenance of chronic pain. Characteristic features of neuroinflammation in chronic pain conditions include infiltration of immune cells into the PNS [e.g., the sciatic nerve and dorsal root ganglion (DRG)], activation of glial cells such as microglia and astrocytes in the CNS (spinal cord and brain), and production and secretion of pro-inflammatory cytokines and chemokines [TNF, interleukin (IL)-1β, IL-6, CCL2, and CXCL1]. Recent studies suggest that bone marrow stem cells or bone marrow stromal cells (BMSCs) produce powerful analgesic effects in animal models of inflammatory pain, neuropathic pain, and cancer pain. We recently demonstrated that intrathecal injection of BMSCs resulted in a long-term relief of neuropathic pain for several weeks after peripheral nerve injury. Strikingly, this analgesic effect is mediated by the anti-inflammatory cytokine transforming growth factor beta secreted from BMSCs. Additionally, BMSCs exhibit potent modulation of neuroinflammation, by inhibiting monocyte infiltration, glial activation, and cytokine/chemokine production in the DRG and spinal cord. Thus, BMSCs control chronic pain by regulation of neuroinflammation in the PNS and CNS via paracrine signaling. In this review, we discuss the similar results from different laboratories of remarkable anti-nociceptive efficacy of BMSCs in animal and clinical studies. We also discuss the mechanisms by which BMSCs control neuroinflammation and chronic pain and how these cells specifically migrate to damaged tissues.

Inclusion complex between β-cyclodextrin and hecogenin acetate produces superior analgesic effect in animal models for orofacial pain

Hecogenin acetate (HA) is a steroidal sapogenin-acetylated with pharmacological properties which have already been described in the literature such as, anti-inflammatory, anti-hyperalgesic and antinociceptive, but it has low solubility in aqueous media. Therefore, in an attempt to overcome this, we set out to create inclusion complexes between HA and b-cyclodextrin (b-CD) and evaluate the antinociceptive effects in the orofacial nociception in mice. The complexes were prepared using different methods in the molar ratios 1:1 and 1:2 and characterized physicochemically. The results of the physicochemical characterization elucidated inclusion complexes formation between b-CD and HA by freeze drying method in the molar ratio 1:2, which obtained a complexation efficiency of 92% and produced superior analgesic effect in animal models for orofacial pain at a lower dose when compared to HA alone.

The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain

Orexins are neuropeptides that are localized to neurons in the lateral and dorsal hypothalamus but its receptors are distributed to many different regions of the central nervous system. Orexins are implicated in a variety of physiological functions including sleep regulation, energy homeostats, and stress reactions. Furthermore, orexins administered exogenously have been shown to have analgesic effects in animal models. A type of intractable pain in patients is pain due to chemotherapy-induced peripheral neuropathy (CIPN). Several chemotherapeutic agents used for the treatment of malignant diseases induce dose-limiting neuropathic pain that compromises patients' quality of life. Here, we examined the analgesic effect of orexin-A in a murine model of CIPN, and compared it with the effect of duloxetine, the only drug recommended for the treatment of CIPN pain in patients. CIPN was induced in male BALB/c mice by repeated intraperitoneal injection of oxaliplatin, a platinum chemotherapeutic agent used for the treatment of advanced colorectal cancer. Neuropathic mechanical allodynia was assessed by the von Frey test, and the effect on acute thermal pain was assessed by the tail flick test. Intracerebroventricularly administered orexin-A dose-dependently attenuated oxaliplatin-induced mechanical allodynia and increased tail flick latencies. Oxaliplatin-induced mechanical allodynia was completely reversed by orexin-A at a low dose that did not increase tail flick latency. Duloxetine only partially reversed mechanical allodynia and had no effect on tail flick latency. The analgesic effect of orexin-A on oxaliplatin-induced mechanical allodynia was completely antagonized by prior intraperitoneal injection of SB-408124 (orexin type-1 receptor antagonist), but not by prior intraperitoneal injection of TCS-OX2-29 (orexin type-2 receptor antagonist). Our findings suggest that orexin-A is more potent than duloxetine in relieving pain CIPN pain and its analgesic effect is mediated by orexin type-1 receptors. Orexin type-1 receptor agonists may have potential therapeutic roles in the treatment of CIPN pain in patients.

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

The μ-opioid receptor (MOR, encoded by Oprm1) agonists are the mainstay analgesics for treating moderate to severe pain. Nerve injury causes down-regulation of MORs in the dorsal root ganglion (DRG) and diminishes the opioid effect on neuropathic pain. However, the epigenetic mechanisms underlying the diminished MOR expression caused by nerve injury are not clear. G9a (encoded by Ehmt2), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined the role of G9a in diminished MOR expression and opioid analgesic effects in animal models of neuropathic pain. We found that nerve injury in rats induced a long-lasting reduction in the expression level of MORs in the DRG but not in the spinal cord. Nerve injury consistently increased the enrichment of the G9a product histone 3 at lysine 9 dimethylation in the promoter of Oprm1 in the DRG. G9a inhibition or siRNA knockdown fully reversed MOR expression in the injured DRG and potentiated the morphine effect on pain hypersensitivity induced by nerve injury. In mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce the expression level of MORs and the morphine effect. In addition, G9a inhibition or Ehmt2 knockout in DRG neurons normalized nerve injury-induced reduction in the inhibitory effect of the opioid on synaptic glutamate release from primary afferent nerves. Our findings indicate that G9a contributes critically to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors may be used to enhance the opioid analgesic effect in the treatment of chronic neuropathic pain.

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

Adenosine kinase (AK) inhibitor is a potential candidate for controlling pain, but some AK inhibitors have problems of adverse effects such as motor impairment. ABT-702, a non-nucleoside AK inhibitor, shows analgesic effect in animal models of pain. Here, we investigated the effects of ABT-702 on synaptic transmission via nociceptive and motor reflex pathways in the isolated spinal cord of neonatal rats. The release of adenosine from the spinal cord was measured by HPLC. ABT-702 inhibited slow ventral root potentials (sVRPs) in the nociceptive pathway more potently than monosynaptic reflex potentials (MSRs) in the motor reflex pathway. The inhibitory effects of ABT-702 were mimicked by exogenously applied adenosine, blocked by 8CPT (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A1 receptor antagonist, and augmented by EHNA (erythro-9-(2-hydroxy-3-nonyl) adenine), an adenosine deaminase (ADA) inhibitor. Equilibrative nucleoside transporter (ENT) inhibitors reversed the effects of ABT-702, but not those of adenosine. ABT-702 released adenosine from the spinal cord, an effect that was also reversed by ENT inhibitors. The ABT-702-facilitated release of adenosine by way of ENTs inhibits nociceptive pathways more potently than motor reflex pathways in the spinal cord via activation of A1 receptors. This feature is expected to lead to good analgesic effects, but, caution may be required for the use of AK inhibitors in the case of ADA dysfunction or a combination with ENT inhibitors.

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain

Objectives:The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the analgesic effects of AS1069562 in rat models of inflammatory and noninflammatory nociceptive pain.Methods:Adjuvant-induced arthritis (AIA) and bradykinin-induced knee joint pain were used as rat models of inflammatory pain. The chronic phase of monoiodoacetate-induced arthritis (MIA) was used as a rat model of noninflammatory pain. Analgesic effects were evaluated by weight-bearing deficit in the AIA and MIA models and by pain response in the bradykinin-induced knee joint pain model.Results:In the AIA model and the bradykinin-induced knee joint pain model, AS1069562 significantly ameliorated the pain-related behavior of weight-bearing deficit and the pain response, respectively. AS1069562 also significantly improved the pain-related behavior of weight-bearing deficit in the chronic phase of the MIA model. Further, following monoiodoacetate injection, repeated administration of AS1069562 or duloxetine significantly improved weight-bearing deficit in the MIA model. Interestingly, the analgesic effect of AS1069562 was sustained for 24 hours after the last administration, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the analgesic effect of duloxetine did not continue after treatment discontinuation.Discussion:AS1069562 exerts analgesic effects on inflammatory and noninflammatory nociceptive pain in rat models of arthritis pain, and repeated administration of AS1069562 exerts a more persistent analgesic effect on arthritis pain than duloxetine. These findings suggest that AS1069562 has an attractive analgesic profile for the treatment of nociceptive pain.