scholarly journals Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

2015 ◽  
Vol 20 (6) ◽  
pp. 321-326 ◽  
Author(s):  
Handong Ouyang ◽  
Peizong Wang ◽  
Wan Huang ◽  
Qiang Li ◽  
Bilin Nie ◽  
...  
Keyword(s):  
Side Effects ◽  
Adrenergic Receptor ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Formalin Injection ◽  
Nociceptive Response ◽  
Sprague Dawley ◽  
Allosteric Site ◽  
Isobolographic Analysis ◽  
Antinociceptive Action

BACKGROUND: Amiloride has been reported to produce a wide variety of actions, thereby affecting several ionic channels and a multitude of receptors and enzymes. Intrathecal α2-adrenergic receptor agonists produce pronounced analgesia, and amiloride modulates α2-adrenergic receptor agonist binding and function, acting via the allosteric site on the α2A-adrenergic receptor.OBJECTIVES: To investigate the antinociceptive interaction of intrathecal amiloride and the α2-adrenoceptor agonist tizanidine using a rat formalin test.METHODS: Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters and were tested for paw flinching using formalin injection. Biphasic painful behaviour was recorded. Amiloride, tizanidine or an amiloride-tizanidine mixture was administered 10 min before formalin injection. To characterize any interactions, isobolographic analysis was performed. The effects of a pretreatment using intrathecally administered yohimbine was also tested.RESULTS: Intrathecally administered amiloride (12.5 μg to 100 μg) and tizanidine (0.5 μg to 5 μg), given separately, produced a significant dose-related suppression of the biphasic responses in the formalin test. Isobolographic analysis revealed that the combination of intrathecal amiloride and tizanidine synergistically reduced phase I and II activities. Intrathecally administered yohimbine antagonized or attenuated the antinociceptive effect of amiloride, tizanidine and the amiloride-tizanidine mixture. Intrathecally administered amiloride synergistically interacts with tizanidine to reduce the nociceptive response in the formalin test, most likely by activating α2-adrenoceptors in the spinal cord.CONCLUSIONS: Although intrathecal tizanidine produced pronounced analgesia, antinociceptive doses of intrathecal tizanidine also produced several side effects, including bradycardia and sedation. Amiloride produced antinociceptive action against the thermal nociceptive test without side effects in rats.

Role of the NO-cGMP-K+ channels pathway in the peripheral antinociception induced by α-bisabolol

2021 ◽  
Author(s):  
Mario I Ortiz ◽  
Raquel Cariño-Cortés ◽  
Victor Manuel Muñoz Pérez ◽  
Andres Salas Casas ◽  
Gilberto Castañeda-Hernández
Keyword(s):  
Opioid Receptors ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
K Channel ◽  
Formalin Injection ◽  
K Channels ◽  
The Right

The aim of this study was to examine if the peripheral antinociception of α-bisabolol involve the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, L-NAME, ODQ, glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-bisabolol produced antinociception during both phases of the formalin test. α-bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-bisabolol was able to active the NO-cGMP-K+ channels pathway in order to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.

Pharmacologic Interaction between Cannabinoid and either Clonidine or Neostigmine in the Rat Formalin Test

2003 ◽  
Vol 99 (3) ◽  
pp. 701-707 ◽  
Author(s):  
Myung Ha Yoon ◽  
Jeong Il Choi
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Formalin Test ◽  
Cannabinoid Receptor ◽  
Phase 1 ◽  
Antinociceptive Effect ◽  
Spinal Level ◽  
Isobolographic Analysis ◽  
Cannabinoid 1 Receptor

Background Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. Methods Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. Results Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). Conclusions Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.

Inhibition of Nociception-induced Spinal Sensitization by Anesthetic Agents 

1995 ◽  
Vol 82 (1) ◽  
pp. 259-266 ◽  
Author(s):  
Therese C. O'Connor ◽  
Stephen E. Abram
Keyword(s):  
Nitrous Oxide ◽  
Formalin Test ◽  
Phase 1 ◽  
Formalin Injection ◽  
Second Phase ◽  
Nociceptive Response ◽  
Phase 2 ◽  
Anesthetic Agents ◽  
C Fiber ◽  
Spinal Sensitization

Background Subcutaneous injection of dilute formalin in the hind paw of the rat produces a biphasic nociceptive response. Initial C-fiber activity is accompanied by flinching of the paw for about 5 min (phase 1), followed by cessation of activity and resumption of flinching beginning 15 min after injection and lasting about 40 min or more (phase 2). The second phase depends on changes in dorsal horn cell function that occur shortly after the initial C-fiber discharge. It was previously shown that isoflurane, administered during phase 1, reduced phase 2 activity, but a combination of isoflurane and nitrous oxide given throughout phase 1 did not suppress spinal sensitization. The same model was used to determine the effects of several inhalation and intravenous anesthetic agents on phase 2 of the formalin test. Methods The formalin test was carried out on male Sprague-Dawley rats. Animals anesthetized briefly with halothane to facilitate formalin injection, were compared to animals that received 1 MAC anesthesia from 5 min before to 6 min after formalin injection using halothane, enflurane, isoflurane, desflurane, or 70% N2O, or a combination of nitrous oxide plus 1 MAC halothane. Animals that were given intravenous saline immediately before injection of formalin were compared to animals given either 20 mg/kg intravenous thiopental just before formalin injection or 10 mg/kg intravenous propofol just before and 3 mg/kg immediately after formalin injection. Flinches/minute were counted at 1 and 5 min after formalin injection and thereafter at 5-min intervals for 1 h. The total of 1- and 5-min flinches were considered phase 1 activity and the total of 10-60-min flinches were considered phase 2. Total phase 2 activity was compared between groups using one-way analysis of variance. Results Animals that received halothane, enflurane, isoflurane, desflurane, or nitrous oxide during phase 1 demonstrated a significant decrease in phase 2 activity when compared to controls, while those that received a combination of nitrous oxide and halothane exhibited no difference. Animals that received intravenous thiopental anesthesia during phase 1 demonstrated no difference in phase 2 activity when compared to controls, whereas those that received propofol during phase 1 demonstrated a significant decrease of phase 2 activity. Conclusions Volatile anesthetics or nitrous oxide significantly suppress spinal sensitization, whereas the combination of nitrous oxide plus halothane causes no suppression. Thiopental does not affect spinal sensitization, whereas propofol causes significant suppression. These results may have important implications regarding the development of postoperative pain.

Analgesic Effect of Electric Stimulation of Peripheral Nerves with Different Electric Frequencies Using the Formalin Test

2000 ◽  
Vol 28 (02) ◽  
pp. 291-299 ◽  
Author(s):  
Ching-Liang Hsieh ◽  
Chi-Chung Kuo ◽  
Yueh-Sheng Chen ◽  
Tsai-Chung Li ◽  
Ching-Tou Hsieh ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Analgesic Effect ◽  
Early Phase ◽  
Electric Stimulation ◽  
Formalin Test ◽  
Late Phase ◽  
Antinociceptive Effect ◽  
Neck Muscle ◽  
Nociceptive Response ◽  
Nociceptive Responses

Although electroacupuncture (EA) has been widely used to treat pain, the optimal frequency of EA therapy remains unclear. The study sought to determine the effect of different EA frequencies in a Sprague-Dawley (SD) rat model of pain. Electric stimulation (ES) at frequencies of 2 Hz, 15 Hz or 100 Hz was applied to the ipsilateral or contralateral sciatic nerve of the injected hindpaw of SD rats. Formalin (50 μl, 5%) was subcutaneously injected into the plantar surface of the left hindpaw to induce a nociceptive response. Behavior, including licking and biting, was observed to have two distinct periods, an early phase during the first 5 mins and a late phase from 21-35 mins after injection. The total biting or licking count served as an Indicator of nociceptive response. Our results indicate that ES of the ipsilateral sciatic nerve at a frequency of 2 Hz or 15 Hz reduced the nociceptive responses in both the early and the late phases of the formalin test, whereas ES at 2 Hz had greater antinociceptive effect than ES at 15 Hz in the early phase. No similar analgesic effect in the early phase was observed for ES at 100 Hz. Both pretreatment with ES at 2 Hz and naloxone (3 mg/kg, s.c.) produced a greater antinociceptive response in the late phase than when ES at 2 Hz was delivered immediately after formalin administration. In addition, ES of the neck muscle or contralateral sciatic nerve at a frequency of 2 Hz also decreased licking and biting activity in both phases. The results of this study indicate that different analgesic mechanisms are involved in the response to ES at frequencies of 2 Hz, 15 Hz and 100 Hz, and that ES at 2 Hz has a greater analgesic effect on formalin-induced nociceptive response, especially when it is delivered prior to the onset of pain. The analgesic effect of ES may be mediated via a central origin in the supraspinal level. These findings suggest that 2 Hz may be a good frequency selection for clinical EA applications in analgesia, and that pretreatment with EA at 2 Hz may be an effective method to treat post-operative pain.

scholarly journals Antinociceptive effects of intrathecal cimifugin treatment: a preliminary rat study based on formalin test

2020 ◽  
Vol 15 (4) ◽  
pp. 478-485
Author(s):  
Hyun Young Lee ◽  
Young Joon Ki ◽  
Su Yeong Park ◽  
Soo Yeon Cho ◽  
Jinyoung Seo ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Formalin Test ◽  
Phase 1 ◽  
Antinociceptive Effect ◽  
Intrathecal Administration ◽  
Phase 2 ◽  
Sprague Dawley ◽  
Antinociceptive Effects ◽  
Saposhnikovia Divaricata ◽  
Rat Study

Background: Cimifugin is one of the components of the root of Saposhnikovia divaricata. The extract derived from S. divaricata is traditionally used as an analgesic. This study was conducted to evaluate the analgesic effect of intrathecal cimifugin in the formalin test.Methods: Male Sprague–Dawley rats (n = 20) were randomized into four groups for intrathecal administration of 70% dimethylsulfoxide and various doses of cimifugin (100 μg, 300 μg, and 1,000 μg). The typical flinch response after the injection of 5% formalin into the hind paw was assessed in two distinct phases: phase 1 until 10 min, and phase 2 from 10 min to 60 min. ED50 values were calculated via linear regression.Results: Intrathecal cimifugin significantly reduced the flinch response in both phases of the formalin test. Significant antinociceptive effects of cimifugin were found with the dose of 300 μg in phase 1 and the dose of 100 μg in phase 2. The ED50 value (95% confidence intervals) of intrathecal cimifugin was 696.1 (360.8–1,342.8) μg during phase 1 and 1,242.8 (42.0–48,292.5) μg during phase 2.Conclusions: Intrathecal cimifugin has an antinociceptive effect against formalin-induced pain. Cimifugin has an anti-inflammatory effect at low concentrations, and non-inflammatory analgesic effect at higher concentrations.

scholarly journals Pharmacokinetic of Diclofenac in the Presence and Absence of Glibenclamide in the Rat

2009 ◽  
Vol 12 (3) ◽  
pp. 280 ◽  
Author(s):  
María R. León-Reyes ◽  
Gilberto Castañeda-Hernández ◽  
Mario I Ortiz
Keyword(s):  
Oral Administration ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Formalin Injection ◽  
Pharmacodynamic Interaction ◽  
Chromatography Method

ABSTRACT - PURPOSE. There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. METHODS. Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS. Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. CONCLUSION. The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.

Synergistic Antinociceptive Effect of Amitriptyline and Morphine in the Rat Orofacial Formalin Test

2004 ◽  
Vol 100 (3) ◽  
pp. 690-696 ◽  
Author(s):  
Philippe Luccarini ◽  
Laurent Perrier ◽  
Céline Dégoulange ◽  
Anne-Marie Gaydier ◽  
Radhouane Dallel
Keyword(s):  
Confidence Interval ◽  
Inflammatory Pain ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Second Phase ◽  
Isobolographic Analysis ◽  
Antinociceptive Effects ◽  
Analgesic Agents ◽  
Rubbing Behavior ◽  
Orofacial Formalin Test

Background Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats. Methods Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline. Results Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. Conclusions The current study suggests that systemic amitriptyline and morphine synergistically inhibit cutaneous orofacial inflammatory pain in rats.

Lateral Hypothalamic-Induced Alpha-Adrenoceptor Modulation Occurs in a Model of Inflammatory Pain in Rats

2009 ◽  
Vol 10 (4) ◽  
pp. 331-339 ◽  
Author(s):  
Younhee Jeong ◽  
Janean E. Holden
Keyword(s):  
Dorsal Horn ◽  
Inflammatory Pain ◽  
Antinociceptive Effect ◽  
Allyl Isothiocyanate ◽  
Spinal Cord Dorsal Horn ◽  
Mustard Oil ◽  
Control Group ◽  
Nociceptive Response ◽  
Sprague Dawley ◽  
Alpha Adrenoceptor

Previous work from our lab showed that stimulation of the lateral hypothalamus (LH) produces analgesia (antinociception) in a model of thermal nociceptive pain. This antinociceptive effect is mediated by α2-adrenoceptors in the spinal cord dorsal horn. However, a concomitant, opposing hyperalgesic (pro-nociceptive) response also occurs, which is mediated by α1-adrenoceptors in the dorsal horn. Antinociception predominates but is attenuated by the pronociceptive response. To determine whether such an effect occurs in a model of inflammatory pain, we applied mustard oil (allyl isothiocyanate; 20 μl) to the left ankle of female Sprague-Dawley rats. We then stimulated the LH using carbamylcholine chloride (carbachol; 125 nmol). The foot withdrawal latencies were measured. Some rats received intrathecal α-adrenoceptor antagonists to determine whether the opposing α-adrenoceptor response was present. Mustard oil application produced hyperalgesia in the affected paw, while the LH stimulation increased the foot withdrawal latencies for the mustard oil paw as compared to the control group. Following carbachol microinjection in the LH, WB4101, an α1-adrenoceptor antagonist, produced significantly longer foot withdrawal latencies compared to saline controls, while yohimbine, an α2-antagonist, decreased the foot withdrawal latencies from 10 min postinjection ( p < .05). These findings support the hypothesis that the LH-induced nociceptive modulation is mediated through an α-adrenoceptor opposing response in a model of inflammatory pain.

scholarly journals Antinociceptive Effects of Spinal Manipulative Therapy on Nociceptive Behavior of Adult Rats during the Formalin Test

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Stephen M. Onifer ◽  
William R. Reed ◽  
Randall S. Sozio ◽  
Cynthia R. Long
Keyword(s):  
Formalin Test ◽  
Antinociceptive Effect ◽  
Spinal Manipulative Therapy ◽  
Formalin Injection ◽  
Nociceptive Behavior ◽  
Adult Rats ◽  
Manipulative Therapy ◽  
Antinociceptive Effects ◽  
Custom Made ◽  
The Mean

Optimizing pain relief resulting from spinal manipulative therapies, including low velocity variable amplitude spinal manipulation (LVVA-SM), requires determining their mechanisms. Pain models that incorporate simulated spinal manipulative therapy treatments are needed for these studies. The antinociceptive effects of a single LVVA-SM treatment on rat nociceptive behavior during the commonly used formalin test were investigated. Dilute formalin was injected subcutaneously into a plantar hindpaw. Licking behavior was video-recorded for 5 minutes. Ten minutes of LVVA-SM at 20° flexion was administered with a custom-made device at the lumbar (L5) vertebra of isoflurane-anesthetized experimental rats (n=12) beginning 10 minutes after formalin injection. Hindpaw licking was video-recorded for 60 minutes beginning 5 minutes after LVVA-SM. Control rats (n=12) underwent the same methods except for LVVA-SM. The mean times spent licking the formalin-injected hindpaw of both groups 1–5 minutes after injection were not different. The mean licking time during the first 20 minutes post-LVVA-SM of experimental rats was significantly less than that of control rats (P<0.001). The mean licking times of both groups during the second and third 20 minutes post-LVVA-SM were not different. Administration of LVVA-SM had a short-term, remote antinociceptive effect similar to clinical findings. Therefore, mechanistic investigations using this experimental approach are warranted.

scholarly journals Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Exert Antinociceptive Activity in the Tail-Flick and Formalin Test in Rodents and Reveal Reduced Gastrotoxicity

2020 ◽  
Vol 21 (24) ◽  
pp. 9685
Author(s):  
Marta Szandruk-Bender ◽  
Benita Wiatrak ◽  
Łukasz Szczukowski ◽  
Piotr Świątek ◽  
Maria Rutkowska ◽  
...  
Keyword(s):  
Formalin Test ◽  
Late Phase ◽  
Antinociceptive Effect ◽  
Tail Flick ◽  
High Dose ◽  
Nociceptive Response ◽  
Tail Flick Test ◽  
Oxadiazole Derivatives ◽  
High Doses ◽  
Derivatives Of

Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.

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