Acetic Acid-induced Visceral Nociception Research Articles

Effect of thymoquinone on acetic acid-induced visceral nociception in rats: role of central cannabinoid and α2-adrenergic receptors.

Thymoquinone (TQ) is the main biologically active substance of Nigella sativa (black seeds). It has anti-cancer, anti-inflammatory, anti-diabetic, anti-oxidative and anti-nociceptive properties. This study was aimed to explore the effect of TQ on acetic acid-induced visceral nociception. The central mechanisms of the effect of TQ were investigated using cannabinergic (AM251) and α2-adrenergic (yohimbine [Yoh]) antagonists. The lateral ventricle of the brain was cannulated for intracerebroventricular (ICV) injections. Visceral nociception was induced by intra-peritoneal (IP) injection of acetic acid (1.00% in a volume of 1.00 mL). Measuring the latency time to the first writhing appearance and counting the number of writhing in 5-min intervals for a period of 60 min were performed. Locomotor activity was determined using an open-field test. Oral administration (PO) of 2.50 and 10.00 mg kg-1 TQ increased the latency time to the first writhing appearance and decreased the number of writhing. The AM251 (5.00 µg per rat; ICV) and Yoh (5.00 µg per rat; ICV) partially prevented TQ (10.00 mg kg-1; PO)-induced anti-nociception. Locomotor activity was not altered by these treatments. The results of the present study showed that TQ had the ability to reduce visceral nociception caused by IP injection of acetic acid. The central mechanisms of this action of TQ might be partially mediated by cannabinergic and α2-adrenegic receptors.

Cerebellar fastigial nucleus histamine and its H2 but not H1 receptors might inhibit acetic acid-induced visceral nociception and improve motor coordination in rats: role of opioid system.

The cerebellum and its deep nuclei contribute to the regulation of important functions including motor coordination and pain. Histamine modulates some functions of the fastigial nucleus (FN) such as motor coordination. In this study, by application of histamine and activation of its H1 and H2 receptors, the FN processing of visceral pain, general locomotor activity and motor coordination were targeted. The possible mechanism of action was followed by the inhibition of opioid receptors. The right and left sides of the FN were surgically implanted with guide cannulas. Immediately after an intraperitoneal injection of acetic acid (1.00 mL, 1.00%), the first writhing onset latency and the writhing number over 60 min were recorded. Open-field and rotarod tests were applied for general locomotor and motor coordination assessment, respectively. Histamine and dimaprit (H2 receptor agonist) increased first writhing onset latency, decreased the writhing number and increased falling time from the rod. These effects were prevented by ranitidine (H2 receptor antagonist) pre-treatment. Significant alterations were not observed by histamine H1 receptor agonist (2-pyridylethylamine) and antagonist (mepyramine). Naloxone, with no effect on falling time from the rod, inhibited the antinociceptive effects of histamine and dimaprit. Beam break number was not affected by the above-mentioned treatments. Based on the results, it can be suggested that histamine H2, but not H1 receptors at the FN might have had an inhibitory role on acetic acid-induced visceral pain and improved motor coordination. The antinociception, but not motor coordination might be mediated by FN opioid receptors.

Effects of the calcium channel blockers Phα1β and ω-conotoxin MVIIA on capsaicin and acetic acid-induced visceral nociception in mice

The effects of intrathecal administration of the toxins Phα1β and ω-conotoxin MVIIA were investigated in visceral nociception induced by an intraperitoneal injection of acetic acid and an intracolonic application of capsaicin. The pretreatments for 2h with the toxins reduced the number of writhes or nociceptive behaviors compared with the control mice. Phα1β administration resulted in an Imax of 84±6 and an ID50 of 12 (5–27), and ω-conotoxin MVIIA resulted in an Imax of 82±9 and an ID50 of 11 (4–35) in the contortions induced by the intraperitoneal injection of acetic acid. The administration of Phα1β resulted in an Imax of 64±4 and an ID50 of 18 (9–38), and ω-conotoxin MVIIA resulted in an Imax of 71±9 and an ID50 of 9 (1–83) in the contortions induced by intracolonic capsaicin administration. Phα1β (100/site) or ω-conotoxin MVIIA (30pmol/site) pretreatments caused a reduction in CSF glutamate release in mice intraperitoneally injected with acetic acid or treated with intracolonic capsaicin. The toxin pretreatments reduced the ROS levels induced by intraperitoneal acetic acid injection. Phα1β, but not ω-conotoxin MVIIA, reduced significantly the ROS levels induced by intracolonic capsaicin administration.Perspective: Phα1β is a ω-toxin with high therapeutic index and a broader action on calcium channels. It shows analgesic effect in several rodents' models of pain, including visceral pain, suggesting that this toxin has the potential to be used in clinical setting as a drug in the control of persistent pathological pain.

Activation of ERK signaling in rostral ventromedial medulla is dependent on afferent input from dorsal column pathway and contributes to acetic acid-induced visceral nociception

Several lines of evidence from both animal and clinical studies have demonstrated that dorsal column (DC) pathway plays a critical role in visceral pain transmission from the spinal cord to supraspinal center. The descending pain modulation pathway from the rostral ventromedial medulla (RVM) area has been implicated in visceral nociceptive neurotransmission. Previous studies have demonstrated that the multiple protein kinase signaling transduction cascades in the RVM area contribute to the descending facilitation of inflammatory pain and neuropathic pain. However, whether these signaling transduction pathways in the RVM area are triggered by the afferent visceral input from the DC pathway during acute visceral pain remains elusive. Here, we have tested the hypothesis that the afferent visceral stimuli from the DC pathway might induce the activation of extracellular signal-regulated protein kinase (ERK) signaling in the RVM area and contribute to the descending facilitation of neurotransmission in a rat model of visceral pain. Our results showed that acetic acid-induced visceral nociception produced a persistent activation of ERK in the RVM area and a microinjection of a mitogen-activated ERK kinase (MEK) inhibitor, U0126, into the RVM area significantly inhibited the visceral noxious stimulation-induced behaviors in rats. A microinjection of lidocaine into the nucleus gracilis (NG) also inhibited the activation of ERK in the RVM area. The current study indicates that activated ERK signaling pathway in the RVM area is dependent on afferent input from dorsal column pathway and may contribute to acetic acid-induced visceral nociception.

Impaired Nociception and Peripheral Opioid Antinociception in Mice Lacking Both Kinin B1 and B2 Receptors

Kinins (e.g., bradykinin) acting through the constitutively expressed B2 and the injury-induced B1 receptors are involved in pain and hyperalgesia, as previously shown by use of receptor-selective antagonists and single-receptor knockout models. Because the overall contribution of kinins to painful processes remains unclear, the aim of this study was to analyze pain-related behaviors of mice unable to respond to kinins because of a lack of both B1 and B2 receptors. In knockout mice lacking both B1 and B2 receptors and in wild-type mice (n = 8-21 per group) the authors assessed nociceptive thresholds to mechanical and heat stimuli (von Frey and Hargreaves tests, respectively) in healthy animals and after induction of inflammatory and neuropathic pain, acid-induced visceral nociception, and modulation of nociceptive responses by peripherally administered opioid agonists. In knockout mice lacking both B1 and B2 receptors baseline nociceptive responses to heat were unaltered, nocifensive responses to bradykinin were abolished, acute acetic acid-induced visceral nociception was reduced by approximately 70% (mean difference: 19.5 writhes/30 min) and heat hypersensitivity in carrageenan-induced paw inflammation was decreased 48 h after injection (mean difference 2.88 s), hypersensitivities in chronic complete Freund's adjuvant-induced paw inflammation or after chronic constriction injury of the sciatic nerve were unchanged, and peripheral μ- and δ-opioid-induced analgesia after chronic constriction injury was reduced by 30-35% (mean differences: μ-agonist: 0.495 g, δ-agonist: 0.555 g). These data suggest that kinins are important for nociception associated with acute short-lasting inflammation but are less essential in chronic stages of pain. The results also highlight a new protective function of kinins via interactions with the opioid system.

Analgesic effects of an ethanol extract of the fruits of Xylopia aethiopica (Dunal) A. Rich (Annonaceae) and the major constituent, xylopic acid in murine models

Background:Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders including rheumatism, headache, colic pain, and neuralgia. Little pharmacological data exists in scientific literature of the effect of the fruit extract and its major diterpene, xylopic acid, on pain. The present study evaluated the analgesic properties of the ethanol extract of X. aethiopica (XAE) and xylopic acid (XA), in murine models.Materials and Methods:XAE and XA were assessed in chemical (acetic acid-induced abdominal writhing and formalin tests), thermal (Tail-flick and Hargreaves thermal hyperalgesia tests), and mechanical (Randall-Selitto paw pressure test) pain models.Results:XAE and XA exhibited significant analgesic activity in all the pain models used. XAE (30-300 mg kg-1, p.o.) and XA (10-100 mg kg-1, p.o.) inhibited acetic acid-induced visceral nociception, formalin- induced paw pain (both neurogenic and inflammatory), thermal pain as well as carrageenan-induced mechanical and thermal hyperalgesia in animals. Morphine (1-10 mg kg-1, i.p.) and diclofenac (1-10 mg kg-1, i.p.), used as controls, exhibited similar anti-nociceptive activities. XAE and XA did not induce tolerance to their respective anti-nociceptive effects in the formalin test after chronic administration. Morphine tolerance did not also cross-generalize to the analgesic effects of XAE or XA.Conclusions:These findings establish the analgesic properties of the ethanol fruit extract of X. aethiopica and its major diterpene, xylopic acid.

Antinociceptive and anti-hypernociceptive effects of Se-phenyl thiazolidine-4-carboselenoate in mice

In this study, the antinociceptive, anti-hypernociceptive and toxic effects of orally administered (R)-Se-phenyl thiazolidine-4-carboselenoate (Se-PTC, 1–50mg/kg) were evaluated in mice. Se-PTC did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels. Furthermore, in an open field test, Se-PTC did not alter the number of crossings and rearing. Se-PTC significantly reduced the amount of writhing when assessed by acetic acid-induced visceral nociception and attenuated the licking time of the injected paw in the early and late phases of a formalin test. In addition, Se-PTC reduced nociception produced by intra-plantar (i.pl.) injection of glutamate, capsaicin, cinnalmaldehyde, bradykinin, phorbol myristate acetate and 8-Bromo-cAMP. Se-PTC caused a significant increase in hot plate and tail-immersion response latencies, but the antinociceptive effect of Se-PTC in the tail immersion was not abolished by pretreatment with the non-selective opioid receptor antagonist, naloxone. Se-PTC (25mg/kg) significantly inhibited nociceptive behavior induced by intrathecal (i.t.) injection of glutamate, N-methyl-d-aspartate (NMDA) and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), but failed to affect nociception induced by kainate and α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA). Mechanical hypernociception induced by carrageenan and Complete Freund's Adjuvant was attenuated by Se-PTC administration. These results indicate that Se-PTC produces antinociception in several models of nociception.

Central effect of histamine on acetic acid-induced visceral nociception in rats

In the present study, the effects of intracerebroventricular (ICV) injections of histamine, chlorpheniramine (H1-receptor antagonist) and ranitidine (H2-receptor antagonist) were investigated on visceral nociception induced by an intraperitoneal (IP) injection of acetic acid in rats. The latency time to the beginning of the first abdominal wall contraction (the first writhe) was recorded and the number of writhes was counted for 1 h after the IP injection of acetic acid (1 ml, 1%). All treatments (histamine: 2.5–80 µg, chlorpheniramine and ranitidine: 5–80 µg) did not influence the latency time to the beginning of the first writhe significantly except for the 40 ?g dose of histamine, which significantly increased the latency time (p

Evidence of TRPV1 receptor and PKC signaling pathway in the antinociceptive effect of amyrin octanoate

Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a synthetic compound derivative from natural precursor α, β-amyrin, against nociceptive response induced by acetic acid and formalin. Here, we investigated some of the mechanisms of action underlying the antinociceptive effects of amyrin octanoate. Amyrin octanoate given intraperitoneally (0.001–1 mg /kg) or intrathecally (10–1000 ng /site) caused dose-dependent and long-lasting inhibition of acetic acid-induced visceral nociception, with mean ID 50 values of 0.003 (0.001–0.005) mg/kg and 122.4 (60.8–246.6) ng/site, respectively. In the capsaicin- and glutamate-induced paw licking, amyrin octanoate caused significant and dose-dependent inhibition of both nociceptive responses, with ID 50 values of 1.36 and 0.04 mg/kg, respectively. Furthermore, amyrin octanoate also reduced significantly the nociception caused by intrathecal injection of glutamate, substance P and capsaicin, with inhibitions of 36 ± 11%, 67 ± 10% and 78 ± 5%, respectively. The antinociception caused by amyrin octanoate in the acetic acid test was significantly attenuated by neonatal pretreatment of mice with capsaicin, but seems to involve mechanisms independent of G i/o protein, opioidergic, serotonergic, noradrenergic and cholinergic system, since it was not affected by pertussis toxin, naloxone, yohimbine, mecamylamine or atropine. In addition, amyrin octanoate reduced thermal and mechanical hyperalgesia induced by bradykinin and phorbol myristate acetate in rats, without affecting similar responses caused by prostaglandin E 2. Taken together, the present results shown that octanoate amyrin produces antinociceptive and antihyperalgesic effects, through an interaction with capsaicin-sensitive fibers and the inhibition of the PKC signaling pathway.

Evidence for a role of 5-HT 1A receptor on antinociceptive action from Geissospermum vellosii

Ethnopharmacological relevance Geissospermum vellosii is a tree widely found throughout the Amazonic forest and frequently used by the native population for painful disorders. Aim of the study The present study examined the antinociceptive effects of Geissospermum vellosii in behavioral models of nociception. Materials, methods and results Oral administration of crude extract of Geissospermum vellosii or its dichloromethane fraction (1–100 mg/kg) inhibited formalin-induced inflammatory nociception and acetic acid-induced visceral nociception. The antinociceptive effect of Geissospermum vellosii was unrelated with motor dysfunctions. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine (0.001–1 mg/kg), isolated from the dichloromethane fraction, also produced antinociception. The antinociception caused by the dichloromethane fraction was significantly attenuated by pre-treatment of mice with p-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days) and WAY-100635 (a 5-HT 1A receptor antagonist, 0.3 mg/kg). In contrast, dichloromethane fraction antinociception was not affected by pre-treatment of animals with ketanserin (a 5-HT 2 receptor antagonist, 0.3 mg/kg) or ondansetron (a 5-HT 3 receptor antagonist, 0.5 mg/kg). Conclusions Together, these results indicate that Geissospermum vellosii produces antinociception through an interaction with 5-HT 1A receptors. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine contributes to the antinociceptive properties reported for Geissospermum vellosii.

Lentinus edodes heterogalactan: Antinociceptive and anti-inflammatory effects

Cold aqueous extraction of basidiocarps (fruiting bodies) of the edible mushroom Lentinus edodes ( shiitake) gave rise to a heteropolysaccharide, whose chemical structure, antinociceptive and anti-inflammatory properties were determined. Its chemical structure was based on monosaccharide composition, methylation analysis, and NMR spectroscopy ( 1H, 13C, HSQC, HSQC-TOCSY, HSQC-NOESY, and coupled HMQC). It was found to be a fucomannogalactan with a main chain of (1 → 6)-linked α- d-galactopyranosyl units, partially substituted at O-2 by single-unit β- d-Man p or α- l-Fuc p side chains. The polysaccharide produced a marked and dose-related effect when assessed against acetic acid-induced visceral nociception. Prevention of peritoneal capillary permeability and leukocyte infiltration caused by the acetic acid was similar in potency and effectiveness.

The Effect of Curcumin (Active Substance of Turmeric)on the Acetic Acid-Induced Visceral Nociception in Rats

In the present study, the effect of chronic oral administration of curcumin in the presence or absence of morphine and noloxone was investigated on the visceral nociception induced by acetic acid in rats. Intraperitoneal injection of acetic acid (1 mL, 2%) produced contractions in the abdominal musculature (writhes). The latency time to the beginning of the first writhe was measured and the total number of writhes in the 1 h after acetic acid injection was counted. The latency time to the beginning of the first writhe was significantly (p < 0.05) increased and the number of writhes was significantly (p < 0.05) decreased by curcumin (20 and 40 mg kg(-1) body weight). The same results were obtained after subcutaneous injection of morphine (1 mg kg(-1) b.wt.). Naloxone at the dose of 1 mg kg(-1) body weight had no effect on pain intensity. Curcumin significantly (p < 0.05) enhanced the effect of morphine on the visceral pain responses, however did not reverse the effect of naloxone. Present data suggest that in the acetic acid-induced visceral nociception of rats, curcumin may produce an antinociceptive effect and the endogenous analgesic opioid system is involved in the curcumin-induced antinociception.

Evidence for the involvement of glutamatergic and GABAergic systems and protein kinase A pathway in the antinociceptive effect caused by p-methoxy-diphenyl diselenide in mice

The present study investigated the antinociceptive effect of p-methoxy-diphenyl diselenide (MeOPhSe) 2, a simple organochalcogenide, in chemical and thermal behavioural models of nociception in mice, without accompanying changes in ambulation when assessed in an open field. This compound given by oral route (p.o.) produced antinociception when assessed on acetic acid-induced visceral nociception, with mean ID 50 value of 9.64 (3.28–28.35) mg/kg. In addition, the per oral administration of (MeOPhSe) 2 exhibited significant inhibition of the neurogenic nociception induced by intraplantar (i.pl.) injection of capsaicin, with mean ID 50 value of 16.29 (11.43–23.22) mg/kg. (MeOPhSe) 2 showed an antinociceptive effect when measured by the tail-immersion and hot-plate tests. Likewise, compound inhibited both neurogenic and inflammatory phases of the overt nociception caused by i.pl injection of formalin, with mean ID 50 values of 22.32 (17.84–27.92) and 19.65 (13.67–28.24) mg/kg, respectively. (MeOPhSe) 2 reduced the nociception produced by i.pl. injection of glutamate and 8-bromo-cAMP (8-Br-cAMP, a protein kinase A [PKA] activator), with mean ID 50 values of 11.05 (7.12–17.15) and 8.72 (5.42–14.02) mg/kg, respectively. (MeOPhSe) 2 also reduced formalin-, glutamate-, induced paw oedema formation. A marked inhibition of the biting behaviour induced by intrathecal (i.t.) injection of glutamate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and (±)-1 aminocyclopentane- trans-1,3-dicarboxylic acid ( trans-ACPD) was caused by (MeOPhSe) 2. However, (MeOPhSe) 2 completely failed to affect the nociception induced by i.t. injection of N-methyl- d-aspartate (NMDA; 450 pmol/site) and kainate (110 pmol /site). The antinociceptive effect caused by (MeOPhSe) 2 was blocked by picrotoxin (a chloride ion channel blocker) and bicucculine (a specific GABA A receptor antagonist) but not by phaclofen (a specific GABA B receptor antagonist) in the hot-plate test. Together, these results indicate that (MeOPhSe) 2 produces antinociception in several models of nociception through mechanisms that involve an interaction with glutamatergic and GABAergic systems, as well as the inhibition of protein kinase A pathway.

Involvement of cellular prion protein in the nociceptive response in mice

The role of the cellular prion protein (PrP c) in neuronal functioning includes neuronal excitability, cellular adhesion, neurite outgrowth and maintenance. Here we investigated the putative involvement of the PrP c function on the nociceptive response using PrP c null ( Prnp 0/0) and wild-type ( Prnp +/+) mice submitted to thermal and chemical models of nociception. PrP c null mice were more resistant than wild-type mice to thermal nociception of the tail-flick test. However, no significant difference was found on the hot plate test. In the acetic acid-induced visceral nociception, PrP c null mice showed an enhanced response when compared to wild-type mice. However, there was no difference between Prnp 0/0 and wild-type mice on glutamate- and formalin-induced licking behaviour and Freund's Complete Adjuvant (FCA)-induced mechanical allodynia. PrP c null mice developed significantly lower paw edema than wild-type mice. In addition, the visceral conditioning stimuli produced by a previous injection of acetic acid (20 days before testing) significantly reduced early and late phases of formalin-induced nociception in wild-type mice. In contrast, the same pre-treatment did not alter the formalin response in PrP c null mice. These results indicate a role of PrP c in the nociceptive transmission, including the thermal tail-flick test and visceral inflammatory nociception (acetic acid-induced abdominal constriction). Our findings show that PrP c is involved with a response mediated by inflammation (paw edema) and by visceral conditioning stimuli.

The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception

Nefopam is a clinically effective analgesic agent used to control mild to moderate pain, whose mechanism of action is unknown. We have investigated the antinociceptive activity of nefopam in the mouse abdominal constriction assay and tail immersion test (48°C). Nefopam was found to possess a high degree of potency against acetic acid-induced visceral nociception (ED 50 2.5 mg kg −1). In the presence of the opioid receptor antagonists, naloxone or naltrindole, the resulting nefopam dose–response relationships were shifted to the right. Naloxone or naltrindole had no effect upon aspirin (ED 50 32.1 mg kg −1) or clonidine (ED 50 0.061 mg kg −1) induced antinociception. Acetorphan (10 mg kg −1; s.c.), an inhibitor of neutral endopeptidase (EC 3.4.24.11) was able to potentiate nefopam's antinociceptive activity (ED 50 1.5 mg kg −1). The α 2-adrenoceptor antagonist, 2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002; 1 mg kg −1; s.c.), shifted the dose–response curves for clonidine (ED 50 7.1 mg kg −1) and nefopam (ED 50 5.3 mg kg −1) to the right in this assay. Additionally, centrally administered RX821002 (1 μg/5 μl/animal; i.c.v.) reduced both clonidine (ED 50 7.2 mg kg −1) and nefopam's (ED 50 15.5 mg kg −1) efficacy in the abdominal constriction assay. Nefopam (3 and 7.5 mg kg −1; s.c.) produced significant antinociceptive effect in the thermal assay. Aspirin and RX821002 were devoid of any significant activity in the tail immersion test. Nefopam was shown to possess RX821002-reversible antinociceptive activity in both the tail immersion test and the abdominal constriction assay. These data suggest the involvement of an opioidergic and noradrenergic component to nefopam's antinociceptive activity in the mouse abdominal constriction assay and tail immersion test. However, the present results are unable to determine if the opioidergic component of nefopam antinociception is through a direct and/or indirect activation of opioid receptors.