benzofurans and Pain

Pain comorbid with depression occurred frequently in clinical settings. This study aims to explore the molecular mechanism underlying antidepressant and analgetic effect of salvianolic acid B (SalB) in comorbid pain in depression induced by chronic restraint stress (CRS), which associates with GABAergic neuron activation in the amygdala and the ERK-CREB-BDNF signaling pathway. The differentially expressed genes related to comorbid pain in CRS-induced depression were screened through bioinformatics analysis. After CRS treatment for 3 weeks, depression-like behaviors were developed in GAD2-tdT mice. The retrograde tracer cholera toxin B subunit combined with retrograde tracer CTB-488 was injected into the parafascicular nucleus of thalamus to project GABAergic neurons to observe the labeling of neurons in the whole brain. After treatment with SalB and ERK-CREB-BDNF signaling pathway inhibitor, CRS mice showed a variety of depression-like behaviors, accompanied by enhanced activity of GABAergic neurons in the amygdala projecting to parafascicular nucleus of thalamus. BDNF underexpression occurred in the CRS mice. Overexpressed BDNF activated ERK-CREB-BDNF signaling pathway to alleviate comorbid pain in CRS-induced depression. After intraperitoneal injection of SalB, the depression-like behaviors and pain threshold in CRS mice were alleviated, the effects of which could be eliminated by ERK-CREB-BDNF signaling pathway antagonist. Collectively, SalB inhibits the excitation of GABAergic neurons in the amygdala and activates the ERK-CREB-BDNF signaling pathway through the parafascicular nucleus of thalamus, whereby alleviating comorbid pain in CRS-induced depression in mice.

Topics: Animals; Benzofurans; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Depression; Extracellular Signal-Regulated MAP Kinases; GABAergic Neurons; Hippocampus; Humans; Mice; Pain; Stress, Psychological

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.

Topics: Analgesics; Animals; Benzofurans; Depression; Disease Models, Animal; Fibromyalgia; Hyperalgesia; Idazoxan; Imidazoles; Imidazoline Receptors; Imidazolines; Male; Pain; Pain Measurement; Quinazolines; Rats; Rats, Sprague-Dawley; Reserpine

The imidazoline I2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 μl) were quantified after treatment with I2 receptor agonists alone or in combination with the I2 receptor antagonist idazoxan. Anatomical mediation was studied by locally administering 2-BFI into the plantar surface or into the right lateral ventricle through cannulae (intracerebroventricular). The locomotor activity was also examined after central (intracerebroventricular) administration of 2-BFI. 2-BFI (1-10 mg/kg, intraperitoneal) and BU224 (1-10 mg/kg, intraperitoneal) attenuated the spontaneous flinching response observed during 10 min (phase 1) and 20-60 min (phase 2) following formalin treatment, whereas CR4056 (1-32 mg/kg, intraperitoneal) decreased only phase 2 flinching response. The I2 receptor antagonist idazoxan attenuated the antinociceptive effects of 2-BFI and BU224 during phase 1, but not phase 2. Peripheral administration of 2-BFI (1-10 mg/kg, intraplantar) to the hind paw of rats had no antinociceptive effect. In contrast, centrally delivered 2-BFI (10-100 µg, intracerebroventricular) dose-dependently attenuated phase 1 and phase 2 flinching at doses that did not reduce the locomotor activity. Together, these data revealed the differential antinociceptive effects of I2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I2 receptor agonist-induced antinociceptive actions.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Imidazoline Receptors; Injections, Intraperitoneal; Injections, Intraventricular; Locomotion; Male; Pain; Pain Measurement; Quinazolines; Rats; Rats, Sprague-Dawley; Time Factors

Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies.. This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen.. Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays.. 2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner.. Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Arthritis, Experimental; Benzofurans; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Imidazoles; Imidazoline Receptors; Imidazolines; Ligands; Male; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reinforcement Schedule

This study examined the effects of imidazoline I2 receptor agonists on the development of tolerance to and physical dependence on repeated morphine treatment in rats.. Two groups of rats (n = 9 per group) were trained to lever press for sucrose (10%) presentation under a fixed-ratio 10 schedule. The rate-suppressing effects of the opioid receptor ligands morphine and naltrexone and the I2 receptor agonist 2-BFI were examined weekly in rats treated with either daily morphine (20 mg·kg(-1) , s.c.), alone or in combination with 2-BFI (10 mg·kg(-1) ) for 3 weeks. Changes in body weight were measured following naltrexone tests in both groups of rats. In separate experiments, the antinociceptive effects of morphine were assessed using a warm-water tail-withdrawal procedure in rats before and after daily treatments (7 days) with morphine (32 mg·kg(-1) , i.p.) alone or in combination with various doses of the I2 receptor agonists 2-BFI, BU224 and CR4056.. Daily treatment for 3 weeks, with morphine in combination with 2-BFI produced significantly less tolerance to the rate-suppressing effects of morphine and produced a decreased sensitivity to the rate-suppressing effects of naltrexone as well as decreased naltrexone-induced weight loss, compared with morphine-alone group. Repeated treatment for 7 days with morphine produced antinociceptive tolerance, which was attenuated by co-administration with 2-BFI, BU224 or CR4056.. Imidazoline I2 receptor agonists attenuated the development of tolerance to and physical dependence on morphine, further supporting the therapeutic potential of combining I2 receptor agonists and opioids for pain treatment.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Body Weight; Drug Tolerance; Imidazoles; Imidazoline Receptors; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Topics: Animals; Benzofurans; CX3C Chemokine Receptor 1; Disease Models, Animal; Encephalitis; Epidermis; Hyperalgesia; Ischemia; Male; Microglia; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Chemokine; Reflex Sympathetic Dystrophy; Spinal Cord Dorsal Horn

Investigation of the pharmacological potential of Tetrahydrofurano/pyrano quinoline and Benzo [b]furoindolyl derivatives in acute inflammation, pain and oxidative stress.. Tetrahydrofurano/ pyrano quinoline and Benzo[b]furoindolyl were evaluated for anti-inflammatory activity by carrageenan-induced hind paw edema in rats. Analgesic activity in mice was assessed by both peripheral and central analgesic models. The free radical scavenging activity of the synthetic compound was analyzed by the in vivo antioxidant assays, by measuring the antioxidant enzymes such as Superoxide dismutase (SOD), Catalase and Peroxidase from the liver homogenate and the in vitro antioxidant activity was evaluated by DPPH photometric assay, Hydroxyl radical scavenging and Lipid Peroxidation assay.. The compounds had substantially inhibited the inflammation induced by subcutaneous carrageenan injection. The same compounds had demonstrated remarkable central and peripheral analgesic activity with potent free radical scavenging activity as evident from both in vitro and in vivo antioxidant assays.. Tetrahydrofurano/pyrano quinoline and Benzo[b]furoindolyl derivatives exhibit varied pharmacological activities that include anti-inflammatory, analgesic and antioxidant activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Benzofurans; Carbon Tetrachloride; Carrageenan; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Design; Edema; Furans; Indoles; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Pain; Quinolines; Rats

Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy.. This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats.. Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs.. Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.), and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations.. Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzofurans; Disease Models, Animal; Drug Synergism; Hyperalgesia; Imidazoles; Imidazoline Receptors; Imidazolines; Inflammation; Ligands; Male; Nociception; Oxycodone; Pain; Protein Binding; Rats; Rats, Sprague-Dawley

Benzofuranone (BF1) was synthesized and its effects evaluated on mechanical hypersensitivity and paw edema models induced by different agents and on neuropathic pain induced by partial ligation of the sciatic nerve. An attempt was also made to elucidate the mechanism of action.. Swiss mice were used for the tests. Hypersensitivity was induced by intraplantar injection of carrageenan, bradykinin (BK), prostaglandin E2 (PGE2), epinephrine, lipopolysaccharide, or complete Freund adjuvant or by using a neuropathic pain model (evaluated with von Frey filament 0.6 g). The antiinflammatory effects were investigated in a paw edema model induced by carrageenan, PGE2, and BK (measured with a plethysmometer). The involvement of protein kinase C (PKC) was investigated through a nociception model induced by phorbol myristate acetate.. BF1 inhibited the hypersensitivity and paw edema induced by intraplantar injection of carrageenan, BK, and PGE2 (P < 0.001), and it was effective in reducing the hypersensitivity evoked by complete Freund adjuvant or epinephrine (P < 0.001) but not by lipopolysaccharide (P = 0.2570). BF1 inhibited the licking behavior induced by phorbol myristate acetate (P < 0.001), suggesting involvement of the PKC pathway. A reduction in hypersensitivity of mice submitted to partial ligation of the sciatic nerve (P < 0.001) was observed, with inhibition of neutrophil migration and interleukin-1β production into the spinal cord. BF1 treatment did not interfere with locomotor activity (P = 0.0783) and thermal withdrawal threshold (P = 0.5953), which are important adverse effects of other analgesics.. BF1 has dose-dependent antihypersensitive and antiinflammatory effects in both acute and chronic models of pain and inflammation, possibly mediated through interference with the PKC activation pathway. The easy and fast synthesis of this compound, low-cost, low-concentration-requirement, and once-daily-administration drug suggest it as a candidate for future clinical studies.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Benzofurans; Disease Models, Animal; Edema; Female; Male; Mice; Pain; Protein Kinase C; Signal Transduction

Ultra-low doses of alpha-2 (α2)-adrenoceptor antagonists augment spinal morphine antinociception and inhibit tolerance, but the role of receptor specificity in these actions is unknown. We used the stereo-isomers of the α2 adrenoceptor antagonist, efaroxan to evaluate the effect of receptor specificity on the induction of spinal morphine tolerance and hyperalgesia. Tail flick and paw pressure tests were first used to evaluate high dose efaroxan (12.6 μg) and its stereo-isomers on clonidine analgesia in intrathecally catheterized rats. Ultra-low doses of individual isomers (1.3 ng) were then co-administered with morphine (15 μg) to determine their effects on acute antinociceptive tolerance and hyperalgesia induced by low dose spinal morphine (0.05 ng). Results demonstrate that high dose (+) efaroxan antagonized clonidine-induced antinociception, while (-) efaroxan had minimal effect. In addition, an ultra-low dose of (+) efaroxan (1.3 ng), substantially lower than required for receptor blockade, inhibited the development of acute morphine tolerance, while (-) efaroxan was less effective. Racemic (±) efaroxan effects were similar to those of (+) efaroxan. Furthermore, low dose morphine (0.05 ng) produced sustained hyperalgesia in the tail flick test and this was blocked by co-injection of (+) but not (-) efaroxan (1.3 ng). Given the isomer-specific efaroxan effects and their different receptor potencies, we suggest that inhibition of opioid tolerance by ultra-low dose efaroxan involves a specific interaction with spinal α2-adrenoceptors in this model. Likewise, inhibitory effects of adrenoceptor antagonists on morphine tolerance may be due to blockade of opioid-induced hyperalgesia.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Antagonists; Analgesics; Animals; Benzofurans; Clonidine; Drug Tolerance; Hot Temperature; Hyperalgesia; Imidazoles; Injections, Spinal; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Touch

Accumulating evidence indicates that imidazoline I(2) receptor agonists enhance the antinociceptive effects of opioids and therefore may be suitable for combination therapy with opioids for pain treatment. However, little is known of the effects of I(2) receptor agonists on other behavioral effects of opioids. This study used schedule-controlled responding and dose-addition analyses to examine interactions between the μ opioid receptor agonist morphine and two imidazoline I(2) receptor agonists, 2-BFI and BU224. In 8 rats responding under a fixed ratio 10 schedule of food presentation, morphine (3.2-17.8 mg/kg), 2-BFI (3.2-17.8 mg/kg), and BU224 (5.6-17.8 mg/kg) each dose-dependently decreased responding. The addition of fixed proportions of 2-BFI or BU224 shifted the morphine dose-effect curves leftward. The interactions between morphine and 2-BFI or BU224 were infra-additive when the same proportions of morphine and I(2) receptor agonists were mixed; however, the interaction between morphine and I(2) receptor agonists was additive when the drugs were mixed at other proportions. These results provide quantitative evidence that I(2) receptor agonists do not enhance the response rate-decreasing effect of morphine and suggest that the enhancement of morphine antinociception is selective. Together, these results further support the therapeutic potential of combining I(2) receptor agonists and opioids for pain control.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Conditioning, Operant; Drug Interactions; Imidazoles; Imidazoline Receptors; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Reinforcement Schedule

Myrsinoic acid B (MAB) is a diprenylated benzoic acid widely found in the vegetal kingdom. Recent studies demonstrate that MAB has important antinociceptive effects in models of chemically or thermally induced nociception in mice.. In the present study we evaluated the effect of MAB in different models of inflammatory and neuropathic hypersensitivity in mice.. This study demonstrates that the pretreatment with MAB, given orally (8.4 to 83.8 μmol/kg), inhibited carrageenan- and complete Freund adjuvant-induced mechanical hypersensitivity. When administered after the induction of hypersensitivity, MAB also reduced the mechanical hypersensitivity in the ipsilateral and in the contralateral hindpaws of mice injected with complete Freund adjuvant, interfering with a signaling cascade already established. MAB reversed the hypersensitivity (mechanical and thermal) of operated animals, with similar results to those observed with gabapentin. MAB activity was evident when administered either systemically (PO or IV) or intrathecally, suggesting interference in the central pathways of pain control. Furthermore, MAB seems to present an antiinflammatory effect evidenced by the interference in both the neutrophil migration and in the increase of interleukin-1β levels after carrageenan injection. Of note, MAB treatment did not interfere with mechanical or thermal sensitivity in healthy mice, a frequent characteristic of commonly used analgesics, such as morphine or gabapentin. Side effects including interference in locomotor activity, motor performance, and body temperature in animals treated with MAB were absent.. MAB reduced mechanical and thermal hypersensitivity in mice submitted to models of inflammatory and neuropathic pain, showing excellent potential for treating persistent pain in humans.

Topics: Administration, Oral; Alkenes; Analgesics; Animals; Behavior, Animal; Benzofurans; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Intravenous; Interleukin-1beta; Mice; Motor Activity; Neuralgia; Neutrophil Infiltration; Pain; Pain Measurement; Pain Threshold; Peroxidase; Time Factors

This work evaluates the antinociceptive properties of benzofuranones using chemically induced models of pain and the hot plate test. All the compounds exhibited significant antinociceptive activity, with 3-[2-(4-chlorophenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3d) being the most active. According to the application of the Topliss method, the 2π-π(2) parameter was the preponderant one, indicating that the hydrophobicity (π) seems to be more involved in the antinociceptive activity. Based on the table of other possible substituents proposed by Topliss, three derived from compound 3d were tested. 3-[2-(3-methoxyphenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3g) showed greater antinociceptive activity with better pharmacokinetic properties predicted. These results show the efficiency of the Topliss Method as a research tool for the discovery of potential candidate molecules for a new antinociceptive drug.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Dose-Response Relationship, Drug; Male; Mice; Molecular Structure; Pain; Pain Measurement; Structure-Activity Relationship

We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Cell Line; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Pain; Rats; Receptors, Prostaglandin E, EP1 Subtype; Structure-Activity Relationship

Pain remains a significant clinical challenge and currently available analgesics are not adequate to meet clinical needs. Emerging evidence suggests the role of imidazoline I(2) receptors in pain modulation primarily from studies of the non-selective imidazoline receptor ligand, agmatine. However, little is known of the generality of the effect to selective I(2) receptor ligands. This study examined the antinociceptive effects of two selective I(2) receptor ligands 2-BFI and BU224 (>2000-fold selectivity for I(2) receptors over α(2) adrenoceptors) in a hypertonic (5%) saline-induced writhing test and analyzed their interaction with morphine using a dose-addition analysis. Morphine, 2-BFI and BU224 but not agmatine produced a dose-dependent antinociceptive effect. Both composite additive curve analyses and isobolographical plots revealed a supra-additive interaction between morphine and 2-BFI or BU224, whereas the interaction between 2-BFI and BU224 was additive. The antinociceptive effect of 2-BFI and BU224 was attenuated by the I(2) receptor antagonist/α(2) adrenoceptor antagonist idazoxan but not by the selective α(2) adrenoceptor antagonist yohimbine, suggesting an I(2) receptor-mediated mechanism. Agmatine enhanced the antinociceptive effect of morphine, 2-BFI and BU224 and the enhancement was prevented by yohimbine, suggesting that the effect was mediated by α(2) adrenoceptors. Taken together, these data represent the first report that selective I(2) receptor ligands have substantial antinociceptive activity and produce antinociceptive synergy with opioids in a rat model of acute pain. These data suggest that drugs acting on imidazoline I(2) receptors may be useful either alone or in combination with opioids for the treatment of pain.

Topics: Adrenergic alpha-2 Receptor Antagonists; Agmatine; Analgesics; Analgesics, Opioid; Animals; Benzofurans; Disease Models, Animal; Drug Synergism; Idazoxan; Imidazoles; Imidazoline Receptors; Ligands; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Yohimbine

Myrsinoic acid B (AMB) is a prenylated-benzoic acid derivative isolated from the Rapanea genus. Recent studies suggest that AMB has antihyperalgesic and antinociceptive properties in different animal models. The present study was designed to investigate the mechanisms involved in antinociception elicited by AMB (60 mg/kg) when administered by intraperitonial route (i.p.) in mice. The antinociceptive response of the compound was characterized by a reduction in contractions of the abdominal muscle, together with stretching of the hind limbs in response to i.p. injection of acetic acid (0.6%, 0.45 ml/mouse). The antinociception caused by AMB in the acetic acid test was significantly attenuated by i.p. treatment of mice with nitric oxide precursor, (L-arginine, 600 mg/kg), alpha2 and alpha1-adrenoceptor antagonists (yohimbine, 0.2 mg/kg/prazosin, 0.2 mg/kg), p-chlorophenylalanine (PCPA) an inhibitor of serotonin synthesis (100 mg/kg), 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN 190), a 5-HT1(A) selective receptor antagonist (0.5 mg/kg) and a non-selective cholinergic antagonist (atropine, 10 mg/kg). Its action was also modulated by the adrenal-gland hormones. In contrast, antinociception was not affected by naloxone (non-selective opioid receptor antagonist, 1.0 mg/kg), phaclofen (2.0 mg/kg) and bicuculline (1.0 mg/kg) GABA(B) and GABA(A) receptor antagonists, respectively, ondansetron (0.3 mg/kg) and ketaserin (1.0 mg/kg), (5-HT3 and 5-HT2 receptors, respectively) and haloperidol (0.2 mg/kg), a non-selective dopaminergic receptor. The antinociceptive effects are not related to muscle-relaxant or sedative action. These results indicate that AMB produces antinociception through mechanisms that involve interaction with L-arginine-nitric oxide, the serotonergic and cholinergic systems, as well as interaction with the alpha-adrenoceptors.

Topics: Alkenes; Animals; Benzofurans; Disease Models, Animal; Male; Mice; Nitric Oxide; Pain; Pain Measurement; Plant Bark; Plant Extracts; Primulaceae; Receptors, Adrenergic, alpha; Receptors, Serotonin; Signal Transduction

The antinociceptive properties of some fractions and two pure compounds, conocarpan and orientin, obtained from P. solmsianum leaves were investigated in several models of pain in mice. The results indicated that this plant exhibits a promising antinociceptive profile, as it produces active principles which are several times more active than some reference drugs used for comparison. The main compound tested, orientin, caused potent and dose-dependent effects against acetic acid-induced writhing and capsaicin- and glutamate-induced nociception, being more effective against the first one, with an ID(50) value of 6.5 mg/kg (14.5 micromol/kg). Orientin was about 20-fold more potent than acetylsalicylic acid and 3.5-fold more active than indomethacin. The antinociceptive effects of this plant may be attributed, at least partially, to the presence of conocarpan and, in particular, to the flavonoid orientin.

Topics: Analgesics; Animals; Benzofurans; Dose-Response Relationship, Drug; Flavonoids; Glucosides; Male; Mice; Pain; Pain Measurement; Piper; Piperaceae; Plant Extracts; Plant Leaves

Chalcones represent an important group of natural or synthetic compounds with a variety of biological activities including antinociceptive and anti-inflammatory ones. The aim of this work was the synthesis of a new benzofuranone compound and evaluation of its antinociceptive potential in mice. The new benzofuranone 4 was synthesized from chalcone 3. The antinociceptive activity of 4 was determined by writhing, formalin, capsaicin, and glutamate and hot-plate tests. Compound 4 caused potent and dose-related inhibition against the writhing test with ID₅₀ 6.1 (5.1-7.6) μmol/kg, i.p., being about 15 times more active than the reference drugs, acetyl salicylic acid and acetaminophen. It was also effective in a dose-dependent manner in significantly reducing the painful stimulus in both phases of formalin, in the capsaicin and in the glutamate test with ID₅₀ values of 27.3 (24.5-30.6) and 18.9 (18.5-19.4) μmol/kg (first and second phase), 12.6 (9.8-16.2) and 24.5 (20.4-29.6) μmol/kg respectively. The results showed that the studied compound exhibits both central and peripheral antinociceptive activities and might be further used as a model to obtain new and more potent analgesic drugs.

Topics: Acetaminophen; Analgesics; Animals; Anti-Inflammatory Agents; Aspirin; Benzofurans; Capsaicin; Chalcone; Dose-Response Relationship, Drug; Formaldehyde; Glutamic Acid; Linear Models; Male; Mice; Nociception; Pain; Pain Measurement

A new series of indanone and aurone derivatives have been synthesized and tested for in vitro AChE inhibitory activity by modified Ellman method. Most of them exhibit AChE inhibitory activities superior to rivastigmine. Further, the most potent compound 1g was selected to evaluate the effect on the acquisition and memory impairment by mice step-down passive avoidance test.

Topics: Animals; Benzofurans; Cholinesterase Inhibitors; Drug Design; Indans; Memory; Mice; Pain; Structure-Activity Relationship

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

Small-conductance Ca(2+)-activated potassium (SK) channels constitute a family of ion channels that are regulated by the cytosolic Ca(2+) concentration. Increases in the intracellular Ca(2+) concentration ([Ca(2+)](i)) result in opening of the channels, which in turn will lead to changes in the membrane potential. As the name implies, the channels are of small conductance, but even so, they are known to play a crucial role in several physiological processes, such as modulation of neurotransmitter and hormone secretion, as well as memory and learning (e.g.,see Curr Med Chem 14:1437-1457, 2007). Owing to the central role of SK channels, they have attracted much attention as potential drug targets, both with respect to identification of activators and blockers of SK channel activity for indications such as, e.g., epilepsy, pain, and urinary incontinence (see Curr Med Chem 14:1437-1457, 2007; Curr Pharm Des 12:397-406, 2006). Thus, great efforts have been put into the development of robust high-throughput assays for detection and characterization of modulators of SK channel activity. In the present chapter, we describe two fluorescence-based Tl(+)influx assays for detection of positive and negative SK channel modulators.

Topics: Benzofurans; Cell Culture Techniques; Cell Line; Epilepsy; Ethers, Cyclic; Humans; Indoles; Ion Channel Gating; Kidney; Membrane Potentials; Oximes; Pain; Small-Conductance Calcium-Activated Potassium Channels; Thallium; Urinary Incontinence

The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the alpha(7)nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant-induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% +/- 4% at 10 mg/kg and 87% +/- 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% +/- 5% at 10 mg/kg and 5% +/- 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant alpha(7)-antagonist methyllycaconitine, which had no effect on agonist activity (90% +/- 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%).. These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzofurans; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Models, Animal; Nicotinic Antagonists; Pain; Pain Measurement; Quinuclidines; Rats; Receptors, Nicotinic; Weight-Bearing

The aim of the study was to investigate the possible role of MK-801, an NMDA antagonist, in analgesia induced by rilmenidine, an imidazoline (I(1)) agonist, in mice in the formalin test.. 25 microl of formalin 2.5% was injected into the dorsal surface of the right hind paw of the mouse. Pain response was scored after formalin injection for a period of 50 min. A weighted average of nociceptive score, ranging from 0 to 3, was calculated. The mean +/-SEM of scores between 0-5 and 15-40 min after formalin injection was presented.. The study showed that rilmenidine (1.25, 2.5 and 5 mg/kg, i.p.) produced analgesia dose-dependently (p<0.001) in formalin test. In addition, the results demonstrated that efaroxan (0.1 and 1 mg/kg, i.p.) could reduce the antinociceptive effect of rilmenidine (2.5 mg/kg, i.p.) (p<0.01) in animals, however, yohimbine (0.1 and 0.2 mg/kg, i.p.) could not block the analgesia induced by rilmenidine (2.5 mg/kg, i.p.) (p>0.05). On the other hand, MK-801 (0.05 mg/kg, i.p.) reduced the pain related behaviors in mice (p>0.05). Moreover, our findings demonstrated that MK-801 (0.01 mg/kg, i.p.) could potentiate the analgesic effect of rilmenidine (1.25 mg/kg, i.p.) significantly (p<0.01).. The present study suggests that imidazoline (I(1)) receptors play an important role in mediating the antinociception induced by rilmenidine in formalin test. Furthermore, it may be concluded that there is an interaction between NMDA receptors and imidazoline (I(1)) binding sites.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics; Animals; Benzofurans; Binding Sites; Binding, Competitive; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Imidazoles; Imidazoline Receptors; Male; Mice; Nervous System; Neurons, Afferent; Nociceptors; Oxazoles; Pain; Pain Measurement; Receptors, Drug; Receptors, N-Methyl-D-Aspartate; Rilmenidine; Yohimbine

Increasing evidence shows that the rostral agranular insular cortex (RAIC) is important in the modulation of nociception in humans and rats and that dopamine and GABA appear to be key neurotransmitters in the function of this cortical region. Here we use immunocytochemistry and path tracing to examine the relationship between dopamine and GABA related elements in the RAIC of the rat. We found that the RAIC has a high density of dopamine fibers that arise principally from the ipsilateral ventral tegmental area/substantia nigra (VTA/SN) and from a different set of neurons than those that project to the medial prefrontal cortex. Within the RAIC, there are close appositions between dopamine fibers and GABAergic interneurons. One target of cortical GABA appears to be a dense band of GABAB receptor-bearing neurons located in lamina 5 of the RAIC. The GABAB receptor-bearing neurons project principally to the amygdala and nucleus accumbens with few or no projections to the medial prefrontal cortex, cingulate gyrus, the mediodorsal thalamic nucleus or contralateral RAIC. The current anatomical data, together with previous behavioral results, suggest that part of the dopaminergic modulation of the RAIC occurs through GABAergic interneurons. GABA is able to exert specific effects through its action on GABAB receptor-bearing projection neurons that target a few subcortical limbic structures. Through these connections, dopamine innervation of the RAIC is likely to affect the motivational and affective dimensions of pain.

Topics: Animals; Benzofurans; Cerebral Cortex; Dopamine; gamma-Aminobutyric Acid; Immunohistochemistry; Interneurons; Limbic System; Male; Neural Inhibition; Neural Pathways; Pain; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Synaptic Transmission; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

Topics: Acetates; Amines; Animals; Benzofurans; Carbamates; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Male; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Rats; Rats, Sprague-Dawley

Moxonidine is a mixed I(1) imidazoline/alpha(2)moxonidine=morphine. The I(1) imidazoline preferring antagonist efaroxan produced a dose-dependent antagonism of both moxonidine (5.0 mg/kg) and clonidine (0.5 mg/kg). In addition, the alpha(2)-adrenergic receptor antagonist yohimbine produced a dose-related antagonism of moxonidine, but only partially antagonized clonidine. Prazosin failed to block the effects of either moxonidine or clonidine, indicating a lack of involvement of alpha(1) as well as alpha(2B) and alpha(2C) receptors. The present results suggest that alpha(2)-adrenergic receptors play an important role in mediating the effects of moxonidine in producing antinociception in the formalin test. Further, the present results demonstrate that the mechanism of action of moxonidine and clonidine differ in that clonidine, but not moxonidine, produces an antinociceptive effect through a yohimbine-insensitive mechanism in the formalin test.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Benzofurans; Clonidine; Dose-Response Relationship, Drug; Formaldehyde; Imidazoles; Imidazoline Receptors; Injections, Subcutaneous; Male; Pain; Pain Measurement; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Drug; Time Factors; Yohimbine

Previous studies have suggested that the alpha2-adrenergic receptor antagonist yohimbine produced antinociceptive effects in the formalin test in rats. However, yohimbine is also an agonist at serotonin (5-HT)1A receptors, suggesting the possibility that the antinociceptive effects of yohimbine might be mediated via these receptors.. The purpose of the present studies was to evaluate the potential role of 5-HT(1A) receptors in mediating the antinociceptive effects of yohimbine.. The antinociceptive effects of yohimbine were evaluated using the formalin test in rats.. Yohimbine (2.5-10 mg/kg s.c.) produced dose-related antinociception during both phase I and phase II of the formalin test, and was approximately equipotent and equiefficacious to morphine. The selective 5-HT(1A) receptor antagonist WAY 100,635 (0.03-3.0 mg/kg s.c.) produced a partial reversal of yohimbine. In comparison, the selective 5-HT(1A) receptor agonist (+/-)8-hydroxy-dipropylaminotetralin HBr (8OH-DPAT; 1.0 mg/kg s.c.) also produced a dose-related antinociception in the formalin test, although 8OH-DPAT was completely reversed by WAY 100,635 (3.0 mg/kg s.c.). The antinociceptive effects of yohimbine were not antagonized by the 5-HT(1B/1D) antagonist GR 127935 (1.0 mg/kg and 3.0 mg/kg s.c.), the 5-HT2 antagonist LY53857 (1.0 mg/kg s.c.), or the 5-HT3 antagonist zatosetron (3.0 mg/kg s.c.).. The present results demonstrate that yohimbine produces a dose-related antinociception in the formalin test in rats which is mediated in part by the agonistic actions at 5-HT(1A) receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-Antagonists; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Ergolines; Formaldehyde; Male; Nociceptors; Oxadiazoles; Pain; Pain Measurement; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors; Yohimbine

CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK(1) receptor antagonists, CP-99,994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK(1) receptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i. c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechanical hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allodynia. Carbamazepine (100 mg/kg) was weakly effective against all the responses. Once daily administration of morphine (3 mg/kg, s. c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of CI-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreover, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 blocked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0.1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic action in the rat rota-rod test. It is suggested that NK(1) receptor antagonists possess a superior side effect profile to carbamazepine and morphine and may have a therapeutic use for the treatment of inflammatory and neuropathic pain.

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Behavior, Animal; Benzofurans; Carbamates; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Guinea Pigs; Hyperalgesia; Male; Mice; Morphine; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sciatic Nerve

A new rat model was established up to evaluate the antinociceptive effect of compounds in visceral pain. The test consisted in measuring the performance of rats in an aversive light stimulus avoidance experimental device. Rats with TNBS-induced colitis had a lower number of total active lever pressings and did not discriminate the active lever from the inactive one. Morphine (1 mg/kg, s.c.) and CI-977 (0.001 mg/kg, s.c.) treatment restored the level of pressing activity of animals and their ability to discriminate the active lever from the inactive one. Naloxone treatment antagonized the improvement of performance produced by morphine. The results obtained indicate that this behavioral paradigm may be used to evaluate the antinociceptive potential of compounds.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzofurans; Cognition; Colitis; Colon; Discrimination, Psychological; Male; Morphine; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Viscera

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity.

Topics: Animals; Benzofurans; Carbamates; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Gerbillinae; Glycine; Guinea Pigs; Humans; Male; Neurokinin-1 Receptor Antagonists; Pain; Pressure; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P

Peritoneal irritation in rats induced by i.p. administration of acetic acid produces abdominal contractions reflecting visceral pain, and gastrointestinal ileus characterized by inhibition of gastric emptying and small intestine transit. In this study, gastric emptying (GE) and intestinal transit, calculated by the geometric center (GC) method, were estimated using a test meal labeled with 51Cr-EDTA. Visceral pain was assessed by counting abdominal contractions. Acetic acid produced abdominal contractions (80.8 +/- 3.3) and inhibition of GE (-54%) and GC (-63%) during the test-period. The kappa-opioid receptor agonists, CI-977 (+/-)-U-50,488H, (+/-)-bremazocine, PD-117,302, (-)-cyclazocine, and U-69,583, reversed abdominal contractions and inhibitions of gastrointestinal transit in a dose-related manner. The mu-opioid receptor agonists and potent analgesics, morphine and fentanyl did not restore normal gastric emptying and intestinal transit. These data suggest that selective kappa-opioid receptor agonists might be used to treat abdominal pain associated with motility and transit impairment during postoperative ileus.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetic Acid; Analgesics; Animals; Benzofurans; Benzomorphans; Cyclazocine; Fentanyl; Gastric Emptying; Intestinal Pseudo-Obstruction; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Peritoneum; Pyrroles; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Thiophenes

CI-977 is a selective, nonpeptide kappa opioid agonist. In rhesus monkeys, CI-977 is a potent antinociceptive agent against thermal stimuli after i.m. administration. Increasing the intensity of the nociceptive stimulus can reduce the analgesic activity of CI-977. Antinociceptive activity also was seen when PD 126212, containing CI-977 as the (-)-enantiomer, was administered sublingually. Naloxone antagonized the antinociceptive action of CI-977, demonstrating opiate receptor involvement in this activity. Monkeys treated with CI-977 also showed sedation at doses close to those required to produce antinociception. As with morphine, the sedative properties of CI-977 were associated with impaired cognitive performance. Aged monkeys appeared more sensitive than young monkeys to the performance-impairing effect of CI-977. Tolerance developed to the antinociceptive and response-suppressing effects. CI-977 was approximately 1000 times more potent than morphine as an analgesic when tested against a moderate (50 degrees C) thermal stimulus but less effective than morphine against a strong (55 degrees C) thermal stimulus.

Topics: Animals; Benzofurans; Cognition; Dose-Response Relationship, Drug; Drug Synergism; Female; Injections, Intramuscular; Macaca mulatta; Male; Morphine; Naloxone; Pain; Pyrrolidines; Receptors, Opioid

The present study examined analgesia produced by S and R isomers of the novel 5-HT3 receptor antagonists, ADR-851 and ADR-882 (0.1-10 mg/kg s.c.) against acute thermal, mechanical and formalin-induced inflammatory pain in rats. Neither isomer of ADR-851 or ADR-882 was analgesic in the thermal or mechanical test. Similarly, neither S or R forms of ADR-882 produced significant anti-nociception in the formalin test. In contrast, ADR-851R produced significant analgesia at 3 and 10 mg/kg doses in this test, while ADR-851S produced significant analgesia only at 1 mg/kg.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Formaldehyde; Inflammation; Male; Metoclopramide; Motor Activity; Nociceptors; Pain; Rats; Rats, Inbred Strains; Respiration; Serotonin Antagonists; Stereoisomerism

IRFI 016 has demonstrated significant antioxidant activity, inhibiting hepatic lipid peroxidation (rat intoxicated by CCl4) and the formation of gastric lesions by ethanol (rat). This activity proved equal to or better than that exhibited by the most investigated antioxidant/radical scavenger agents (such as BHA, BHT, Vitamin E). The drug markedly increased mucus production (rabbit, mouse) by all the administration routes used (os, i.v. and inhalatory) and proved more active than, or overlapping, the most noted mucoregulatory/mucolytic drugs (sobrerol, bromexine, thiopronine, ambroxol, N-acetylcysteine) which were chosen for comparison. The tracheo-bronchial mucus viscosity was also significantly reduced (bronchitic animals) as was the fucose and total protein content. In the pigeon, IRFI 016 improved mucociliary clearance. Moreover IRFI 016 evidenced anti-inflammatory activity nearly equal to that exhibited by ASA and phenylbutazone (carrageenin oedema, abcesses and inflammatory pain).

Topics: Abscess; Animals; Antioxidants; Benzofurans; Bronchi; Carbon Tetrachloride Poisoning; Carrageenan; Columbidae; Edema; Ethanol; Expectorants; Female; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred Strains; Mucus; Pain; Rabbits; Rats; Rats, Inbred Strains; Stomach; Trachea; Vitamin E

Nociceptive tail flick latencies (TFL) were recorded in response to noxious thermal stimuli applied to lightly anaesthetized rats. The effects of intrathecally administered dopamine receptor agonists alone and combined with dopamine receptor antagonists were examined upon the TFL. Experiments were repeated on animals made supersensitive to dopamine following withdrawal from 28 day administration of haloperidol. In untreated animals the D2-receptor agonist LY 171555 and apomorphine produced an increase in TFL. In contrast, the Di-receptor agonist SKF 38393 had no significant effect on TFL. TFL. Following haloperidol-induced dopamine-supersensitivity, SKF 38393 produced an increase in TFL. In contrast, LY171555 and apomorphine had minimal effects on TFL in this preparation. In animals not treated with haloperidol, the dopamine receptor antagonists SCH 23390 and (+/-)-sulpiride both blocked the increase in TFL produced by the D2-agonists. SCH23390 and (+/-)-sulpiride also blocked the increase in TFL produced by SKF 38393 in haloperidol-supersensitized animals. The antinociceptive action of intrathecally administered dopamine agonists appears to be mediated via D2-receptors. Whether the antinociception produced by SKF 38393 is exclusively contingent upon the activation of D1-receptors in the dopamine-supersensitive animal is as yet unresolved.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Benzazepines; Benzofurans; Dopamine Antagonists; Haloperidol; Male; Pain; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spinal Cord; Sulpiride

After injection of true blue (TB) into the pericardial sac and nuclear yellow (NY) into the left ulnar nerve of rats, most perikarya in the left eighth cervical and first thoracic dorsal root ganglia are single-labeled with either TB or NY. However, 7.1-14.7% of the sensory perikarya from the cardiac area labeled with TB are simultaneously labeled with NY. This finding indicates that some primary sensory perikarya receive processes from both the left arm and the heart. In addition to other mechanisms that may be operative in the referral of pain of cardiac origin to the medial left arm, these results suggest that sensory neurons with dichotomizing somatic and visceral peripheral processes may also contribute to this phenomenon.

Topics: Afferent Pathways; Angina Pectoris; Animals; Benzimidazoles; Benzofurans; Female; Ganglia, Spinal; Heart Conduction System; Neurons, Afferent; Pain; Rats; Rats, Inbred Strains; Sensation; Ulnar Nerve

Rats were treated with amiodarone (20 mg/kg/day) up to 6 weeks and the neurotoxicity was assessed by determining changes in motor coordination, pain-threshold and rectal temperature every week during treatment. Body weight gain was decreased during amiodarone treatment and it was significant at and after 5 weeks. Food intake and water consumption were significantly reduced during treatment. After the first week of treatment with amiodarone, rats showed decreased ability to balance on horizontal rods. In the hot plate test (paw-lick), the amiodarone treated rats showed increased pain-thresholds throughout the treatment. Hypothermia was significant only at 6 weeks. These results show that amiodarone causes toxicity in rats and this model might be useful for further studies. Decreased motor-coordination, and increased pain-responding times may indicate development of peripheral neuropathy in addition to muscle weakness.

Topics: Amiodarone; Animals; Benzofurans; Body Temperature; Body Weight; Drinking Behavior; Feeding Behavior; Male; Motor Skills; Nervous System Diseases; Pain; Rats; Rats, Inbred Strains

Fifty-three patients with hypertrophic cardiomyopathy who had serious arrhythmias (45 patients), refractory chest pain (5 patients) or a high risk of sudden death (3 patients) received amiodarone for 6 to 96 months (median 18) after completion of a loading and an initial maintenance period. The dose of amiodarone was altered by 50 to 200 mg/day at 3- to 6-month intervals, guided by electrocardiographic monitoring, plasma drug level measurements and side-effect questionnaires. Ventricular tachycardia was suppressed in 24 patients (92%) with doses of 100 to 400 mg/day (median 300); none died suddenly during a mean follow-up of 27 months. Although symptomatic episodes of frequent or prolonged supraventricular tachycardia or paroxysmal atrial fibrillation/flutter were abolished in 8 of 9 patients on 100 to 600 mg/day (median 300), in 1 patient incessant atrial flutter developed that was relatively refractory to direct-current cardioversion. In 11 patients with atrial fibrillation, sinus rhythm was restored in 7 (after direct-current cardioversion in 3) with doses of 100 to 600 mg/day (median 300) and has been maintained in 5 with associated improvement in symptoms. Despite discontinuation of beta-blocker therapy, chest pain was unchanged in 17 patients, was impaired in 11 and was worse in only 2. Amiodarone was discontinued in 3 patients; in 1 because of hair loss, in 1 because of neurologic symptoms and in 1 because of facial discoloration; in the latter 2 patients, amiodarone was restarted after 1 and 14 months, and was tolerated and effective at the lower dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Atrial Fibrillation; Benzofurans; Cardiomyopathy, Hypertrophic; Echocardiography; Electrocardiography; Heart Rate; Humans; Middle Aged; Pain; Thorax

Topics: Adult; Aged; Analgesics; Benzofurans; Benzoxepins; Face; Female; Headache; Humans; Male; Middle Aged; Pain; Vascular Headaches

Topics: Benzofurans; Female; Humans; Hyperthyroidism; Joint Diseases; Middle Aged; Neurologic Manifestations; Pain; Pyramidal Tracts; Spinal Cord Diseases; Uricosuric Agents

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Angiography; Anticoagulants; Benzofurans; Coronary Angiography; Coumarins; Dipyridamole; Exercise Test; Glucose Tolerance Test; Glycolates; Humans; Myocardial Infarction; Nitrites; Nitroglycerin; Pain; Thoracic Diseases; Vasodilator Agents

Topics: Adult; Aged; Angina Pectoris; Antihypertensive Agents; Benzofurans; Coronary Disease; Drug Combinations; Drug Tolerance; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pain