Effects of Radolmidine, A Novel α2-Adrenergic Agonist Compared with Dexmedetomidine in Different Pain Models in the Rat

2000 ◽  
Vol 93 (2) ◽  
pp. 473-481 ◽  
Author(s):  
Mei Xu ◽  
Vesa K. Kontinen ◽  
Eija Kalso
Keyword(s):  
Neuropathic Pain ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Pharmacokinetic Profile ◽  
Intrathecal Administration ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Test ◽  
Alpha2 Adrenoceptor ◽  
Carrageenan Inflammation

Background Intrathecally administered alpha2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel alpha2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls. Methods Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 microg, 2.5 microg, 5 microg, and 10 microg. Results In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 microg or 5 microg of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 microg dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine. Conclusions Radolmidine and dexmedetomidine had equipotent antinociceptive effects in all tests studied. However, radolmidine caused significantly less sedation than dexmedetomidine, probably because of a different pharmacokinetic profile.

scholarly journals The Effects of Ketamine and Its Enantiomers on the Morphine- or Dexmedetomidine-induced Antinociception after Intrathecal Administration in Rats

2000 ◽  
Vol 93 (1) ◽  
pp. 231-241 ◽  
Author(s):  
Gabriella Joó ◽  
Gyöngyi Horvath ◽  
Walter Klimscha ◽  
Gabriella Kekesi ◽  
Ildiko Dobos ◽  
...  
Keyword(s):  
Time Course ◽  
Antinociceptive Effect ◽  
Motor Impairment ◽  
Intrathecal Administration ◽  
Fixed Dose ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Male Wistar Rats ◽  
Racemic Ketamine ◽  
Alpha2 Adrenoceptor

Background The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and alpha2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexmedetomidine. Methods Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 microg), morphine (0.1-3.0 microg), dexmedetomidine (0.3-10.0 microg), and mixtures of two doses of ketamines (30 or 100 microg) with different doses of morphine or dexmedetomidine for fixed-dose analysis. Results Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 microg (95% confidence interval: 1.04-2.32) and 4. 85 microg (3.96-5.79), respectively. A low dose (30 microg) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 microg racemic ketamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. Conclusions These data indicate that racemic ketamine and S(+)-ketamine, but not R(-)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.

scholarly journals Modulation of Morphine-induced Antinociception in Acute and Chronic Opioid Treatment by Ibudilast

2009 ◽  
Vol 111 (6) ◽  
pp. 1356-1364 ◽  
Author(s):  
Tuomas O. Lilius ◽  
Pekka V. Rauhala ◽  
Oleg Kambur ◽  
Eija A. Kalso
Keyword(s):  
Cell Activation ◽  
Antinociceptive Effect ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Test ◽  
Glial Cell Activation ◽  
Sprague Dawley Rats ◽  
Antinociceptive Effects

Background Opioid analgesics are effective in relieving chronic pain, but they have serious adverse effects, including development of tolerance and dependence. Ibudilast, an inhibitor of glial activation and cyclic nucleotide phosphodiesterases, has shown potential in the treatment of neuropathic pain and opioid withdrawal. Because glial cell activation could also be involved in the development of opioid tolerance in rats, the authors studied the antinociceptive effects of ibudilast and morphine in different models of coadministration. Methods Antinociception was assessed using male Sprague- Dawley rats in hot plate and tail-flick tests. The effects of ibudilast on acute morphine-induced antinociception, induction of morphine tolerance, and established morphine tolerance were studied. Results Systemic ibudilast produced modest dose-related antinociception and decreased locomotor activity at the studied doses of 2.5-22.5 mg/kg. The highest tested dose of 22.5 mg/kg produced 52% of the maximum possible effect in the tail-flick test. It had an additive antinociceptive effect when combined with systemic morphine. Coadministration of ibudilast with morphine did not attenuate the development of morphine tolerance. However, in morphine-tolerant rats, ibudilast partly restored morphine-induced antinociception. Conclusions Ibudilast produces modest antinociception, and it is effective in restoring but not in preventing morphine tolerance. The mechanisms of the effects of ibudilast should be better understood before it is considered for clinical use.

Analgesic Effect of Electroacupuncture on Paclitaxel-Induced Neuropathic Pain via Spinal Opioidergic and Adrenergic Mechanisms in Mice

2015 ◽  
Vol 43 (01) ◽  
pp. 57-70 ◽  
Author(s):  
Jung-Wan Choi ◽  
Suk-Yun Kang ◽  
Jae-Gyun Choi ◽  
Dong-Wook Kang ◽  
Soo-Jin Kim ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Opioid Receptor ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Antagonist ◽  
Spinal Dorsal ◽  
Alpha2 Adrenoceptor

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.

scholarly journals NSAID Antinociception Measured in a Chemical and a Thermal Assay in Mice

2001 ◽  
Vol 6 (4) ◽  
pp. 190-196 ◽  
Author(s):  
HF Miranda ◽  
J Lopez ◽  
F Sierralta ◽  
A Correa ◽  
G Pinardi
Keyword(s):  
Dose Response ◽  
Intrathecal Administration ◽  
Test Subject ◽  
Tail Flick ◽  
Response Curves ◽  
Tail Flick Test ◽  
Chemical Test ◽  
Writhing Test ◽  
Nociceptive Stimulus ◽  
Dose Response Curves

The antinociceptive activity of several nonsteroidal anti-inflammatory drugs (NSAIDs) that were administered either intraperitoneally or intrathecally was assessed in mice by two algesiometric tests. The first was the writhing test, which assessed the abdominal constrictions that were induced by intraperitoneal acetic acid (a chemical test), and the second was the tail flick test, which measured pain responses to heat stimuli. The corresponding effective doses and their relative potencies were compared because these tests use different nociceptive stimuli with different transmission pathways. The intraperitoneal and intrathecal dose-response curves for the antinociception induced by every NSAID that was tested were parallel in the writhing test. In the tail flick test, however, only the intraperitoneal and intrathecal dose-response curves for ketoprofen, piroxicam, naproxen, nimesulide, paracetamol and diclofenac were parallel. The results obtained in this study confirm that NSAIDs possess different abilities to induce inhibition of cyclooxygenase, and they can be indirectly assessed by their different antinociceptive activities, depending on the algesiometric assays that are used. The antinociception of most NSAIDs might involve central mechanisms. The findings demonstrate the increasing importance of the spinal cord in processing and modulating nociceptive input, because intrathecal administration of NSAIDs is always more effective (in terms of potency) than systemic administration; thus, the antinociceptive efficacy of NSAIDs strongly depends on the algesiometric assay that is used and on the type of the nociceptive stimulus to which the test subject is exposed.

scholarly journals Effects of peripheral FAAH blockade on NTG-induced hyperalgesia—evaluation of URB937 in an animal model of migraine

Cephalalgia ◽  
2015 ◽  
Vol 35 (12) ◽  
pp. 1065-1076 ◽  
Author(s):  
R Greco ◽  
T Bandiera ◽  
AS Mangione ◽  
C Demartini ◽  
F Siani ◽  
...  
Keyword(s):  
Animal Model ◽  
Antinociceptive Effect ◽  
Acid Amide ◽  
Male Rats ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Brain Nuclei ◽  
Nociceptive Responses ◽  
Fos Expression ◽  
Baseline Conditions

Background Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)—the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. Aim We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. Results During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. Conclusions The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.

Nitrous Oxide Lacks the Antinociceptive Effect on the Tail Flick Test in Newborn Rats

2000 ◽  
Vol 91 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Masahiko Fujinaga ◽  
Ryan Doone ◽  
M. Frances Davies ◽  
Mervyn Maze
Keyword(s):  
Nitrous Oxide ◽  
Antinociceptive Effect ◽  
Tail Flick ◽  
Newborn Rats ◽  
Tail Flick Test

Antinociceptive Profiles of Platycodin D in the Mouse

2004 ◽  
Vol 32 (02) ◽  
pp. 257-268 ◽  
Author(s):  
Seong-Soo Choi ◽  
Eun-Jung Han ◽  
Tae-Hee Lee ◽  
Ki-Jung Han ◽  
Han-Kyu Lee ◽  
...  
Keyword(s):  
Antinociceptive Effect ◽  
Control Level ◽  
Tail Flick ◽  
Triterpene Saponins ◽  
Tail Flick Test ◽  
Platycodin D ◽  
Pain Models ◽  
Antinociceptive Effects ◽  
Dose Dependent ◽  
Higher Doses

Platycodin D (PD), one of several triterpene saponins, was isolated from roots of Platycodon grandiflorum. We previously reported that intracerebroventricular (i.c.v.) administration of PD showed an antinociceptive effect as measured by the tail-flick assay. However, its exact role in the regulation of antinociception in the various types of pain models has not yet been characterized. Thus, we attempted to find antinociceptive profiles of PD in various pain models. PD administered intraperitoneally (i.p.), i.c.v. or intrathecally (i.t.) showed antinociceptive effects in dose-dependent manners as measured by the tail-flick, writhing and formalin tests. In the tail-flick test, PD at the low doses reached the peak after 15 minutes and returned to the control level after 60 minutes. However, higher doses of PD showed a strong antinociception at least for 1 hour. PD administered i.t. showed stronger antinociception than that induced by i.c.v. administration PD in both tail-flick and writhing tests. In the formalin test, PD administered i.p., i.c.v. or i.t. showed antinociceptive effects during both the first (direct nociceptive stimulation) and second (late inflammatory) phases. Pretreatment with naltrexone i.p., i.c.v. or i.t. did not affect PD-induced inhibition of the tail-flick response. Our results suggest that PD shows a strong antinociceptive effect on the tail-flick, writhing and formalin tests, acting on central nervous system. However, PD-induced antinociception may not be mediated by the opioid receptors.

scholarly journals Nuclear PPAR-γ Activation Modulates Inflammation and Oxidative Stress in Attenuating Chemotherapy-Induced Neuropathic Pain in Vivo

2021 ◽  
pp. 167-179
Author(s):  
Haritha Pasupulati ◽  
Satyanarayana S. V. Padi ◽  
Sujatha Dodoala ◽  
Prasad V. S. R. G. Koganti
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Mechanical Allodynia ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Ppar Γ ◽  
Markers Of Inflammation ◽  
And Oxidative Stress

Background: Paclitaxel-induced painful neuropathy is a major dose-limiting side effect and can persist for up to two years after completing treatment that greatly affects both the course of chemotherapy and quality of life in cancer patients. Peroxisome proliferator-activated receptor (PPAR)-γ belongs to a family of nuclear receptors known for their transcriptional and regulatory roles in metabolism, inflammation, and oxidative stress. However, the role of PPAR-γ activation on paclitaxel-induced neuropathic pain is not yet known. Objective: To investigate whether pioglitazone, a PPAR-γ agonist reduce paclitaxel-induced neuropathic pain and to elucidate underlying mechanisms. Methodology: Peripheral neuropathy was induced by administration of paclitaxel (2 mg/kg per injection) intraperitoneally on four alternate days (days 0, 2, 4, 6). Thermal hyperalgesia and mechanical allodynia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pioglitazone did not induce hypoalgesia and had no effect on locomotor activity. Repeated oral administration of pioglitazone (10 and 20 mg/kg,) for 2 weeks started 14 days after paclitaxel injection markedly attenuated paw withdrawal responses to thermal (hyperalgesia) and mechanical (allodynia) stimuli. Further, pioglitazone administration significantly reduced elevated level of pro-inflammatory cytokine, TNF-α, in both the dorsal root ganglia and the spinal cord accompanied by marked decrease in oxidative stress parameters as well as increase in activity of antioxidant defense enzyme, superoxide dismutase, in the spinal cord after paclitaxel injection. Conclusion: The results of the present study demonstrate that pioglitazone, a PPAR-γ agonist exerted antinociceptive effect in paclitaxel-induced neuropathic pain through inhibiting neuroimmune inflammation in both the periphery and spinal cord and by reducing nitroso-oxidative stress in spinal cord. Our findings strongly suggest pharmacological activation of PPAR-g as a promising therapeutic target in paclitaxel-induced peripheral neuropathy and provide rationale for the clinical evaluation.

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