Comparative antioxidant and analgesic effect of sesame oil, fish oil and their combination in experimental animal model.

Natural oils are rich in polyunsaturated fatty acids (PUFs) like omega 3, omega 6 and other nutrients that boost physical and mental health. Traditionally these oils have been used to treat joint pain associated with several inflammatory conditions. In this study, we investigated the antioxidant and analgesic properties of the sesame oil (SO), fish oil (FO) and combination of these two oils (SO+FO). Different concentrations of the SO, FO and SO+FO combination 0.02-4mg/ml were used for assessing the free radical scavenging activity by DPPH method and the IC50 value was calculated. Acetic acid-induced abdominal writhing test, tail immersion and hot plate models were used to determined analgesic effect. Results showed that both oils were well tolerated as no signs of toxicity or death were noticed during the observational study period. SO+FO combination showed the best antioxidant properties as shown by DPPH assay. Similarly in analgesic models, SO and FO significantly reduced the number of abdominal contractions (p<0.05) however, SO+FO (1:1) exhibited highly significant results (p<0.001) in writhing reflex test. Furthermore, SO and FO both increased the reaction time on a hot plate as well as in tail flick test (p<0.05) whereas, SO+FO significantly increased reaction time (p<0.001) in hot plate and in tail flick test as compared to SO and FO single treatments. Conclusively, our results suggest that the combination of both oils (SO+FO) exhibited significant antioxidant and analgesic potential that it could be considered as one of the active combinations for relieving pain in adjunctive treatment for joint pain associated with rheumatoid arthritis.

Effects of the aqueous extract of Phyllanthus niruri Linn during pregnancy and lactation on neurobehavioral parameters of rats' offspring.

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri L. (Phyllanthaceae) is a plant used in traditional medicine, mainly to treat kidney stones. However, the effects of maternal exposure to P. niruri remain poorly explored. AIM OF THE STUDY: The objective of this study was to investigate the effects of administration of aqueous extract of P. niruri (AEPN) during pregnancy and lactation, in maternal toxicity, reflex maturation, and offspring memory. MATERIALS AND METHODS: Pregnant rats were divided into three groups (n = 8/group): Control (vehicle), AEPN 75, and AEPN 150 (each respectively treated with P. niruri at a dose of 75 and 150 mg/kg/day). The animals were treated via intragastric gavage during pregnancy and lactation. Weight gain, feed intake, and reproductive performance were analyzed in the mothers. In the offspring, the following tests were performed: Neonatal Reflex Ontogeny, Open Field Habituation Test and the Object Recognition Test in adulthood. RESULTS: Maternal exposure to AEPN did not influence weight gain, feed intake, or reproductive parameters. In the offspring, anticipation of reflex ontogenesis (time of completion) was observed (p < 0.05). During adulthood, the AEPN groups presented decreases in exploratory activity upon their second exposure to the Open Field Habituation Test (in a dose-dependent manner) (p < 0.05). In the Object Recognition Test, administration of the extract at 75 and 150 mg/kg induced significant dose-dependent improvements in short and long-term memory (p < 0.05). CONCLUSION: Administration of the AEPN accelerated the reflex maturation in neonates, and improved offspring memory while inducing no maternal or neonatal toxicity.

Variation of spacer type and topology of phenyl moiety in 2-pyridone core of 4-oxo-3-N-methylcytisine; effect of synthesized compounds on rat's behavior in conditioned passive avoidance reflex (CPAR) test.

Novel derivatives of 4-oxo-3-methylcytisine with phenyl moiety bonded to starting molecule through various spacers were obtained from the 9-amino, -halo, -formyl and 11-halo precursors by reductive alkylation of amines, generation of amide, as well as thio- and carboxamide functions, cross-coupling reactions, aldehyde condensation and reduction of unsaturated 'C-C' bonds. Ability of synthesized compounds to influence the learning and memory was preliminary assessed in conditioned passive avoidance reflex (CPAR) test in rats. It was shown, that derivatives with phenyl group at 11 carbon atom influence the learning and memory in CPAR test more effectively than other compounds. The hit-compound (3-methyl-11-(2-phenylvinyl)-3,5,6-trihydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-4,8(1H)-dione) with the best values of 'latency' and 'time spent in the dark compartment' has been identified as a perspective scaffold for synthesis of novel derivatives of (-)-cytisine with potential neuropharmacological activity.

Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome.

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.

Comparison of Adrenaline and Dexmedetomidine in Improving the Cutaneous Analgesia of Mexiletine in Response to Skin Pinpricks in Rats.

BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 µmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 µmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 µmol), adding Dex or Adr to Mex (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 µmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 µmol) alone. A high dose of Adr is more effective with Mex 1.8 µmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 µmol combined with any dose of Adr is superior to that of Dex. CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

Milk Fat Globule Membrane Supplementation in Formula-fed Rat Pups Improves Reflex Development and May Alter Brain Lipid Composition.

Human milk contains nutritional, immunoprotective and developmental components that support optimal infant growth and development. The milk fat globule membrane (MFGM) is one unique component, comprised of a tri-layer of polar lipids, glycolipids, and proteins, that may be important for brain development. MFGM is not present in most infant formulas. We tested the effects of bovine MFGM supplementation on reflex development and on brain lipid and metabolite composition in rats using the "pup in a cup" model. From postnatal d5 to d18, rats received either formula supplemented with MFGM or a standard formula without MFGM; a group of mother-reared animals was used as reference/control condition. Body and brain weights did not differ between groups. MFGM supplementation reduced the gap in maturation age between mother-reared and standard formula-fed groups for the ear and eyelid twitch, negative geotaxis and cliff avoidance reflexes. Statistically significant differences in brain phospholipid and metabolite composition were found at d13 and/or d18 between mother-reared and standard formula-fed groups, including a higher phosphatidylcholine:phosphatidylethanolamine ratio, and higher phosphatidylserine, glycerol-3 phosphate, and glutamine in mother-reared compared to formula-fed pups. Adding MFGM to formula narrowed these differences. Our study demonstrates that addition of bovine MFGM to formula promotes reflex development and alters brain phospholipid and metabolite composition. Changes in brain lipid metabolism and their potential functional implications for neurodevelopment need to be further investigated in future studies.

Protective effects of Withania somnifera extract in SOD1G93A mouse model of amyotrophic lateral sclerosis.

Withania somnifera (WS; commonly known as Ashwagandha or Indian ginseng) is a medicinal plant whose extracts have been in use for centuries in various regions of the world as a rejuvenator. There is now a growing body of evidence documenting neuroprotective functions of the plant extracts or its purified compounds in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Based on the extract's beneficial effect in a mouse model of ALS with TDP-43 proteinopathy, the current study was designed to test its efficacy in another model of familial ALS. Our results show that administration of WS extracts by gavage to mice expressing G93A mutant form of superoxide dismutase (SOD1) resulted in increased longevity, improved motor performance and increased number of motor neurons in lumbar spinal cord. The WS treatment caused substantial reduction in levels of misfolded SOD1whereas it enhanced expression of cellular chaperons in spinal cord of SOD1G93A mice. WS markedly reduced glial activation and prevented phosphorylation of nuclear factor kappaB (NF-κB). The overall immunomodulatory effect of WS was further evidenced by changes in expression of multiple cytokines/chemokines. WS also served as an autophagy inducer which may be beneficial at early stages of the disease. These results suggest that WS extracts might constitute promising therapeutics for treatment of ALS with involvement of misfolded SOD1.

Modulation of Neurally Mediated Vasodepression and Bradycardia by Electroacupuncture through Opioids in Nucleus Tractus Solitarius.

Stimulation of vagal afferent endings with intravenous phenylbiguanide (PBG) causes both bradycardia and vasodepression, simulating neurally mediated syncope. Activation of µ-opioid receptors in the nucleus tractus solitarius (NTS) increases blood pressure. Electroacupuncture (EA) stimulation of somatosensory nerves underneath acupoints P5-6, ST36-37, LI6-7 or G37-39 selectively but differentially modulates sympathoexcitatory responses. We therefore hypothesized that EA-stimulation at P5-6 or ST36-37, but not LI6-7 or G37-39 acupoints, inhibits the bradycardia and vasodepression through a µ-opioid receptor mechanism in the NTS. We observed that stimulation at acupoints P5-6 and ST36-37 overlying the deep somatosensory nerves and LI6-7 and G37-39 overlying cutaneous nerves differentially evoked NTS neural activity in anesthetized and ventilated animals. Thirty-min of EA-stimulation at P5-6 or ST36-37 reduced the depressor and bradycardia responses to PBG while EA at LI6-7 or G37-39 did not. Congruent with the hemodynamic responses, EA at P5-6 and ST36-37, but not at LI6-7 and G37-39, reduced vagally evoked activity of cardiovascular NTS cells. Finally, opioid receptor blockade in the NTS with naloxone or a specific µ-receptor antagonist reversed P5-6 EA-inhibition of the depressor, bradycardia and vagally evoked NTS activity. These data suggest that point specific EA stimulation inhibits PBG-induced vasodepression and bradycardia responses through a µ-opioid mechanism in the NTS.

Local anesthetic effect of docosahexaenoic acid on the nociceptive jaw-opening reflex in rats.

Although docosahexaenoic acid (DHA) administration suppresses sodium channels in primary afferent sensory neurons, the acute local effect of DHA on the trigeminal nociceptive reflex remains to be elucidated, in vivo. Therefore, the aim of the present study was to investigate whether local administration of DHA attenuates the nociceptive jaw-opening reflex (JOR) in vivo in the rat. The JOR evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1-5 x threshold). At 3 x threshold, local administration of DHA (0.1, 10 and 25 mM) dose-dependently inhibited the dEMG response, and lasted 40 min. Maximum inhibition of the dEMG signal amplitude was seen within approximately 10 min. The mean magnitude of inhibition of the dEMG signal amplitude by DHA (25 mM) was almost equal to the local anesthetic, 1% lidocaine (37 mM), a sodium channel blocker. These findings suggest that DHA attenuates the nociceptive JOR via possibly blocking sodium channels, and strongly support the idea that DHA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception.

Pharmacological sensitivity of reflexive and nonreflexive outcomes as a correlate of the sensory and affective responses to visceral pain in mice.

Pain encompasses both sensory and affective dimensions which can be differentially modulated by drugs. Here, we compare the pharmacological sensitivity of the sensory and affective responses using acetic acid-induced abdominal writhings (sensory-reflexive outcome) and acetic acid-induced depression of reward seeking behaviour (RSB, affective-nonreflexive outcome) to a highly palatable food in mice. We found that the expression of RSB critically depends on factors such as sex and previous knowledge and type of the food stimulus. Intraperitoneal administration of acetic acid (iAA) produced a long-lasting (beyond the resolution of writhing behaviour) and concentration-dependent decrease on both appetitive-approach and consummatory dimensions of RSB. Ibuprofen and diclofenac were much more potent in reversing AA-induced changes in RSB: latency to eat (ED50 = 2 and 0.005 mg/kg, intraperinoneally, respectively) and amount consumed (ED50 = 11 and 0.1 mg/kg) than in AA-induced writhing (ED50 = 123 and 60 mg/kg). Morphine and duloxetine inhibited the writhing response (ED50 = 0.8 and 6 mg/kg, respectively) but not the AA-induced changes in RSB. Caffeine was ineffective in both AA-induced writhing and RSB changes. Overall, this study characterized a preclinical mouse model of hedonic deficits induced by pain that can be used to assess affective responses as well as complementary classic reflexive approaches in the evaluation of candidate analgesics.

Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.

OBJECTIVES: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain. METHODS: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5). RESULTS: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12. CONCLUSIONS: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

Oral administration of curcumin attenuates visceral hyperalgesia through inhibiting phosphorylation of TRPV1 in rat model of ulcerative colitis.

Background Curcumin has been reported to have anti-inflammatory and anti-nociceptive effects. The present study was designed to explore the potential therapeutic effects of curcumin on visceral hyperalgesia and inflammation in a rat model of ulcerative colitis. We observed the effects of orally administered curcumin on the disease activity index, histological change in colon, colorectal distension-induced abdominal withdrawal reflex, the expression of transient receptor potential vanilloid 1 (TRPV1) and phosphorylated TRPV1 in dextran sulfate sodium-induced colitis rats. In addition, a HEK293 cell line stably expressing human TRPV1 (hTRPV1) was used to examine the effects of curcumin on the change in membrane expression of TRPV1 induced by phorbol myristate acetate (a protein kinase C activator). Results Repeated oral administration of curcumin inhibited the increase in abdominal withdrawal reflex score induced by dextran sulfate sodium without affecting dextran sulfate sodium-induced histological change of colon and the disease activity index. A significant increase in colonic expression of TRPV1 and pTRPV1 was observed in dextran sulfate sodium-treated rats and this was reversed by oral administration of curcumin. TRPV1 expression in L6-S1 dorsal root ganglion was increased in the small- to medium-sized isolectin B4-positive non-peptidergic and calcitonin gene-related peptide-positive peptidergic neurons in dextran sulfate sodium-treated rats and oral administration of curcumin mitigated such changes. In the HEK293 cell line stably expressing hTRPV1, curcumin (1, 3 µm) inhibited phorbol myristate acetate-induced upregulation of membrane TRPV1. Conclusion Oral administration of curcumin alleviates visceral hyperalgesia in dextran sulfate sodium-induced colitis rats. The anti-hyperalgesic effect is partially through downregulating the colonic expression and phosphorylation of TRPV1 on the afferent fibers projected from peptidergic and non-peptidergic nociceptive neurons of dorsal root ganglion.

QX-OH, a QX-314 derivative agent, produces long-acting local anesthesia in rats.

QX-314 has been shown to produce long-acting local anesthesia in vivo in animals; however, translation to humans has been impeded by concerns about toxicity. We investigated whether the newly emerged QX-OH molecule could confer long-lasting anesthesia with a low local toxicity in rats. In rat sciatic nerve block model, QX-OH 25mM produced a longer sensory block than QX-314 25mM (median [25th, 75th percentiles], 5.5 [4.25, 6] h vs. 3 [3, 4] h; P=0.03). QX-OH 35mM produced a longer sensory block than QX-314 35mM (8 [6, 12] h vs. 6 [4, 6.5] h, P=0.038). QX-OH at 35 and 45mM generated longer motor blocks than QX-314, with tissue toxicity less than that of QX-314 at the same concentration. In contrast with bupivacaine, QX-OH was clearly superior in terms of sensory and motor blockade durations after a single bolus injection. There was no significant difference in tissue toxicity between QX-OH (25 and 35mM) and bupivacaine. In rat cutaneous trunci pinprick model, the QX-OH-induced pain threshold remained significantly different from baseline at 6h (25mM, P<0.0001), 10h (35mM, P<0.0001), and 12h (45mM, P<0.0001). The time required for full recovery from the subcutaneous anesthetic effect was significantly longer for QX-OH than for QX-314 and bupivacaine. So QX-OH produced concentration-dependent, reversible, and long-acting local anesthesia in animal models with a moderate local toxicity.

Oral l-tyrosine supplementation augments the vasoconstriction response to whole-body cooling in older adults.

NEW FINDINGS: What is the central question of this study? Ageing is associated with altered sympathetic responses to stress, which are explained in part by reduced noradrenergic function. The impact of supplementation with oral l-tyrosine, the amino acid precursor for catecholamine synthesis, on the effector responses to cold and exercise stress has yet to be examined. What is the main finding and its importance? Oral l-tyrosine ingestion augmented the sympathetically mediated vasoconstriction response to cold exposure in aged skin. This suggests that l-tyrosine supplementation might improve thermoregulatory function in older adults. l-Tyrosine is the primary substrate for noradrenaline biosynthesis within sympathetic axon terminals. In stressful conditions requiring increased catecholamine production, the axonal l-tyrosine concentration may limit the full expression of the sympathetic effector response and this may be particularly evident in older adults. We hypothesize that oral l-tyrosine supplementation will increase the sympathetic response to whole-body cooling and muscle metaboreflex activation. In a randomized, double-blind design, 11 young (Y = 24 ± 1 years) and 11 older participants (O = 68 ± 4 years) ingested either 150 mg kg-1 of l-tyrosine or placebo before commencing 30 min of whole-body cooling to induce a gradual decline in skin temperature from 34 to 30.5°C. Laser Doppler flux (LDF) was measured at the ventral forearm, and cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percentage change from baseline (%ΔCVC). Two minutes of static hand-grip exercise (35% maximal voluntary contraction) followed by 3 min of postexercise ischaemia were implemented before and toward the end of the cooling bout. l-Tyrosine supplementation did not affect blood pressure or heart rate responses to exercise or postexercise ischaemia. However, the blunted vasoconstriction response to whole-body cooling in older adults (placebo: Y = 39 ± 5%ΔCVC and O = 16 ± 2 %ΔCVC; P < 0.05) was augmented after l-tyrosine supplementation (l-tyrosine: Y = 40 ± 4%ΔCVC and O = 32 ± 5 %ΔCVC; P < 0.05). These results suggest that l-tyrosine bioavailability might limit thermoregulatory function in an older population.

Influence of clove oil and eugenol on muscle contraction of silkworm (Bombyx mori).

Clove oil is used in fish anesthesia and expected to have a mechanism via glutamic receptor. The present study explores the activities of clove oil and its major compound, eugenol, in comparison with L-glutamic acid on glutamic receptor of silkworm muscle and fish anesthesia. It was found that clove oil and eugenol had similar effects to L-glutamic acid on inhibition of silkworm muscle contraction after treated with D-glutamic acid and kainic acid. Anesthetic activity of the test samples was investigated in goldfish. The results demonstrated that L-glutamic acid at 20 and 40 mM could induce the fish to stage 3 of anesthesia that the fish exhibited total loss of equilibrium and muscle tone, whereas clove oil and eugenol at 60 ppm could induce the fish to stage 4 of anesthesia that the reflex activity of the fish was lost. These results suggest that clove oil and eugenol have similar functional activities and mechanism to L-glutamic acid on muscle contraction and fish anesthesia.

In vivo cough suppressive activity of pectic polysaccharide with arabinogalactan type II side chains of Piper nigrum fruits and its synergistic effect with piperine.

Piper nigrum L. fruits are not only a prized spice, but also highly valued therapeutic agent that heals many ailments including asthma, cold and respiratory problems. Herein, we have investigated structural features and in vivo antitussive activity of three fractions isolated from Piper nigrum fruits. The water extract (PN-WE) upon fractionation with EtOH yielded two fractions: a soluble fraction (PN-eSf) and a precipitated (PN-ePf) one. The existence of a pectic polysaccharide with arabinogalactan type II side chains (147kDa) in PN-ePf and piperine in PN-eSf were revealed. Moreover, oligosaccharides providing fine structural details of side chains were generated from PN-ePf and then characterized. The parental water extract (PN-WE) that contained both pectic polysaccharide and piperine, after oral administration (50mgkg-1 body weight) to guinea pigs, showed antitussive activity comparable to codeine phosphate (10mgkg-1 body weight). The EtOH precipitated fraction (PN-ePf) containing pectic polysaccharide showed comparatively higher antitussive activity than EtOH soluble fraction (PN-eSf) that contained piperine, but their potencies are lower than the parental water extract. Significantly, the specific airway smooth muscle reactivity of all three fractions remained unchanged. Finally, pectic polysaccharide-piperine combination in parental extract synergistically enhances antitussive effect in guinea pigs.

Systemic administration of the dietary constituent resveratrol inhibits the nociceptive jaw-opening reflex in rats via the endogenous opioid system.

The aim of the present study was to investigate whether, under in vivo conditions, systemic administration of resveratrol could attenuate the rat nociceptive jaw-opening reflex (JOR) via the endogenous opioid system. The JOR evoked by electrical stimulation of the tongue was recorded as digastric muscle electromyograms (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG increased significantly in proportion to the intensity of electrical stimulation (from 1× to 5 × threshold for the JOR). dEMG amplitude in response to 3× threshold electrical stimulation of the tongue was dose-dependently inhibited by intravenous administration of resveratrol (0.5-2mg/kg). Maximum inhibition of dEMG amplitude was seen within approximately 10min. These inhibitory effects were reversible, with dEMG responses returning to control levels after approximately 20min. Pretreatment of rats with naloxone resulted in significant, dose-dependent attenuation of the inhibitory effects of resveratrol on dEMG amplitude compared with control. These findings suggest that resveratrol inhibits the nociceptive JOR via the endogenous opioid system. Further, the findings of the present study strongly support the idea that resveratrol, which is not known to have any toxic side effects, combined with an opioid could be a potential therapeutic agent for the prevention of acute trigeminal nociception.

Involvement of opioid receptors in inhibition of bladder overactivity induced by sacral neuromodulation in pigs: A possible action mechanism.

AIMS: To determine the role of opioid receptors in the inhibition of bladder overactivity by sacral neuromodulation (SNM) in pigs, and explore the possible mechanism of SNM. METHODS: Both implant-driven stimulators of the S3 spinal nerve were implanted in seven pigs. Naloxone and tramadol were administered. Multiple cystometrograms were performed to determine the effects of SNM and opioid receptors on the micturition reflex by infusing normal saline (NS) or acetic acid (AA). RESULTS: AA-induced bladder overactivity significantly reduced the bladder capacity (BC) to 29.9 ± 3.9% of the NS control level (413.1 ± 55.4 mL) (P < 0.01). SNM significantly increased the BC to 39.4 ± 5.5% of the NS control level (P < 0.03). In the absence of SNM, the cumulative dose of naloxone (0.02 and 0.2 mg/kg intravenously) did not significantly change the BC (25.1 ± 3.1% and 20.2 ± 3.1% of the NS control level, respectively) (P > 0.05). In the presence of SNM, both doses of naloxone significantly reduced the BC to 27.2 ± 3.0% and 25.1 ± 2.9% of the NS control level (P < 0.05), respectively. In the absence of SNM, tramadol did not significantly change the BC (31.5 ± 3.9% of the NS control level) (P > 0.05). In the presence of SNM, tramadol significantly increased the BC to 49.1 ± 6.1% of the NS control level (P < 0.01). CONCLUSIONS: Opioid receptors play a role in inhibition of bladder overactivity during SNM. Combining SNM with tramadol could be a novel treatment modality for overactive bladder.

Pilomotor function is impaired in patients with Parkinson's disease: A study of the adrenergic axon-reflex response and autonomic functions.

INTRODUCTION: Autonomic nervous system disturbances including sweating abnormalities and cardiovascular symptoms are frequent in Parkinson's disease (PD) and often precede motor involvement. Cholinergic vasomotor and sudomotor skin nerves are impaired in patients with PD even at early disease stages. We hypothesized that adrenergic pilomotor nerve function is similarly impaired in early PD and might constitute a novel diagnostic target. METHODS: We conducted a study in 12 PD patients (Hoehn&Yahr 1-2) and 12 healthy control subjects. Pilomotor function was evaluated after iontophoresis of phenylephrine on the dorsal forearm to elicit axon-reflex mediated pilomotor erection (goose bumps). Silicone impressions were obtained, scanned and quantified for pilomotor muscle impressions by number, area and axon-reflex spread. Vasomotor function was evaluated using laser Doppler flowmetry and sudomotor function via sympathetic skin response. Cardiac autonomic function was assessed via heart rate variability. Severity of autonomic symptoms was evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic questionnaire. RESULTS: Pilomotor response was reduced in PD patients compared to control subjects (impression number: 12.2 ± 8.2 vs. 16.5 ± 5.9, p < 0.05; impression area: 10.8 ± 2.2 mm2 vs. 24.8 ± 3.1 mm2, p < 0.01; axon-reflex spread: 89.0 ± 10.6 mm2 vs. 185.9 ± 10.8 mm2, p < 0.01) and correlated negatively with severity of autonomic symptoms (p < 0.01). Similarly, sudomotor (p < 0.01) and vasomotor (p < 0.05) but not cardiac autonomic (p = n.s.) function were reduced in PD patients versus control subjects. CONCLUSION: Pilomotor function is impaired in early stages of PD. Pilomotor axon-reflex assessment might be useful in the investigation of disease related pathology and supplement other clinical markers of autonomic neuropathy in PD.