Characterization of the Antinociceptive and Pronociceptive Effects of Methadone in Rats

2007 ◽  
Vol 106 (3) ◽  
pp. 563-571 ◽  
Author(s):  
Joseph R. Holtman ◽  
Elzbieta P. Wala
Keyword(s):  
Pain Sensitivity ◽  
Opioid Analgesics ◽  
Antagonistic Activity ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Mu Opioid ◽  
Aspartate Receptor ◽  
Opioid Induced Hyperalgesia ◽  
Morphine Hyperalgesia

Background Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities. Methods The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model. Results Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor. Conclusion The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.

scholarly journals Analgesic activity of allopurinol and febuxostat in experimental animals

2018 ◽  
Vol 7 (4) ◽  
pp. 603
Author(s):  
Yajnesh P. Sahu ◽  
Sachchidanand Pandey ◽  
Sabita Mohapatra
Keyword(s):  
Acetic Acid ◽  
Analgesic Activity ◽  
Physical Dependence ◽  
Experimental Pain ◽  
Opioid Analgesics ◽  
Analgesic Nephropathy ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Analgesic Effects ◽  
Peripheral Analgesia

Background: Currently, two classes of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are used to manage pain in different clinical situations. Chronic uses of these drugs have various adverse effects like gastric ulceration/bleeding, analgesic nephropathy and respiratory depression, physical dependence, addiction, respectively. Xanthine oxidase inhibitors, used for chronic gout, might have a role in alleviation of pain, as per literature survey. Hence, the present study was carried out to evaluate the potential analgesic activity of allopurinol and febuxostat in different experimental models.Methods: The analgesic activity of allopurinol and febuxostat was assessed by employing two different experimental pain models-tail flick latency model in rats for central analgesia and acetic acid induced writhing model in mice for peripheral analgesia and was compared with tramadol and aspirin.Results: Allopurinol and febuxostat produced significant central and peripheral analgesic effects as is evident from increase in reaction time in tail flick test and inhibition in number of writhes in acetic acid induced writhing test.Conclusions: The results of the present study demonstrate marked analgesic effect of allopurinol and febuxostat.

scholarly journals Heparin sensitization of fentanyl initiated mu-receptors

2021 ◽  
pp. 20-32
Author(s):  
А.Е. Khomutov ◽  
◽  
А.V. Deryugina ◽  
А.S. Lizunova ◽  
Z.V. Bobrova ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Anticoagulant Activity ◽  
Antinociceptive Effect ◽  
Regulatory Peptides ◽  
Tail Flick ◽  
Mu Opioid Receptors ◽  
Opioid Agonist ◽  
Hypotensive Action ◽  
Tail Flick Test ◽  
Mu Opioid

Heparin is an anticoagulant widely used in clinical practice. In addition to anticoagulant activity, heparin has a cytostatic, bacteriostatic, antilipemic, radioprotective effect, and exhibits antiallergic and hypotensive action. Heparin modulates cardiotropic, neurotropic, antihypoxic, anti-ischemic properties of regulatory peptides and pharmacological agents used in pain relief and anesthesia. At the same time, there is very little information about the antinociceptive effect of heparin. The aim of this work is to study the effect of heparin in combination with the opioid agonist fentanyl on mu-opioid receptors at the spinal and supraspinal levels. In experiments on laboratory rats, it was established that heparin, when pre-administered and combined with fentanyl, increases the latency in the tail flick test and the paw licking test. Naloxone, an opioid receptor antagonist, reduces antinociceptive efficacy of the studied compounds. Protamine sulfate also reduces the level of heparin sensitization of opioid receptors. Thus, the obtained data allow us to speak about the sensitizing effect of heparin on initiated by an agonist mu-opioid receptors at the spinal and supraspinal levels.

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.

scholarly journals Changes in the nociceptive response to thermal stimulation in rats following administration of N-terminal analogs of the adrenocorticotropic hormone

2019 ◽  
pp. 33-36
Author(s):  
S.A. Dodonova ◽  
I.I. Bobyntsev ◽  
A.E. Belykh ◽  
L.A. Andreeva ◽  
N.F. Myasoedov
Keyword(s):  
Pain Sensitivity ◽  
Adrenocorticotropic Hormone ◽  
Biological Effects ◽  
Intraperitoneal Administration ◽  
Regulatory Peptides ◽  
Structural Analog ◽  
Tail Flick ◽  
Nociceptive Response ◽  
Tail Flick Test ◽  
Wide Range

Melanocortins (MCs) are an increasingly studied class of regulatory peptides exerting a wide range of biological effects. All naturally occurring MCs share a His-Phe-Arg-Trp fragment (HFRW) corresponding to the sequence of amino acid residues 6–9 of the adrenocorticotropic hormone (ACTH6-9), which is also a central active component of ACTH. Attaching the Pro-Gly-Pro (PGP) sequence to the C-end of the peptide extends the duration of the peptide’s effect. The aim of this study was to investigate the effects of ACTH6-9-PGP (HFRWPGP) on the spinal and supraspinal mechanisms involved in the nociceptive response in rats and to compare them to those of its structural analog ACTH4-7-PGP (MEHFPGP). ACTH6-9-PGP effects were studied following the intraperitoneal administration of the peptide at doses 0.5, 1.5, 5, 15, 50, 150, or 450 μg/kg 15 minutes before the hot plate and tail flick tests. ACTH4-7-PGP effects were studied under the same conditions at the following doses: 50, 150 and 450 μg/kg. We found that ACTH6-9-PGP administered intraperitoneally at 5 or 150 μg/kg induced a pronounced reduction in pain sensitivity 15 and 45 minutes after the injection (p = 0.04); this effect was implemented via supraspinal mechanisms. In the tail flick test, 150 μg/kg ACTH6-9-PGP increased pain sensitivity, with the participation of segmental spinal mechanisms (p = 0.04). ACTH4-7-PGP did not have any effect on the studied mechanisms of pain sensitivity. Thus, unlike ACTH4-7-PGP, ACTH6-9-PGP can both increase pain sensitivity and exert an analgesic effect.

scholarly journals Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

2021 ◽  
Vol 7 (3) ◽  
pp. 41-47
Author(s):  
Alexander A. Spasov ◽  
Olesya Iu. Grechko ◽  
Natalya V. Eliseeva ◽  
Yuliya V. Lifanova ◽  
Angelina N. Aleksandrenkova
Keyword(s):  
Analgesic Activity ◽  
Analgesic Effect ◽  
Opioid Analgesics ◽  
Benzodiazepine Receptor ◽  
Tail Flick ◽  
Opioid Agonist ◽  
Tail Flick Test ◽  
Kappa Agonist ◽  
Kappa Opioid Agonist ◽  
Probable Interaction

Introduction: Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-1205. Materials and methods: A probable interaction between RU-1205, morphine and adjuvant drugs in pain behaviors was carried out on the model of somatogenic pain. 95 male mice received either RU-1205 (5 mg/kg, i.p.) and morphine (1 mg/kg, i.p.) separately or in combination with haloperidol (0.45 mg/kg, i.p.); midazolam (0.3 mg/kg, i.p.); diazepam (1 mg/kg, i.p.); metoclopramide (5 mg/kg, i.p.), and clonidine (1 mg/kg, i.p.). The analgesic effect was assessed by tail flick test. Registration of the latent period of the reaction was carried out 30, 60 and 90 minutes after the adjuvant drug administration. Results: When studying the interaction with morphine, it was found that clonidine, haloperidol and metoclopramide enhanced the effects; diazepam offset them, and midazolam had no affect on the analgesic properties. In the course of the studies, RU-1205 showed an increase in analgesic activity when combined with clonidine, a slight increase with midazolam, and a decrease when co-administered with diazepam. Haloperidol had no influence on the effect of RU-1205, while metoclopramide both potentiated and reduced the analgesic effect. Discussion: Pharmacodynamic and pharmacokinetic interactions of RU-1205 with an α2AR agonist, benzodiazepine receptor agonists, D2P antagonist, and σ-receptor blocker were established. Conclusion: The presented data make it possible to more accurately formulate ideas about the localization and action mechanism of the kappa-agonist of opioid receptors, the compound RU-1205.

scholarly journals Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Marianna Murányi ◽  
Resat Cinar ◽  
Orsolya Kékesi ◽  
Erika Birkás ◽  
Gabriella Fábián ◽  
...  
Keyword(s):  
Day Treatment ◽  
Antinociceptive Effect ◽  
Parent Compound ◽  
Subcellular Fractions ◽  
Tail Flick ◽  
Surface Binding ◽  
Tail Flick Test ◽  
Mu Opioid ◽  
Biased Agonism ◽  
Regulatory Processes

Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue,cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min afterintracerebroventricular (icv)administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeatedicvinjection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”.

Ketamine Attenuates and Reverses Morphine Tolerance in Rodents

1996 ◽  
Vol 85 (6) ◽  
pp. 1357-1366. ◽  
Author(s):  
Naohito Shimoyama ◽  
Megumi Shimoyama ◽  
Charles E. Inturrisi ◽  
Kathryn J. Elliott
Keyword(s):  
Morphine Tolerance ◽  
Fold Increase ◽  
Response Analysis ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Aspartate Receptor ◽  
Tenfold Increase ◽  
Reverse Tolerance ◽  
Before And After ◽  
Development Of Tolerance

Background The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. Method Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. Results Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. Conclusions Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.

scholarly journals Systemic Lipopolysaccharide-Induced Pain Sensitivity and Spinal Inflammation Were Reduced by Minocycline in Neonatal Rats

2018 ◽  
Vol 19 (10) ◽  
pp. 2947 ◽  
Author(s):  
Cheng-Ta Hsieh ◽  
Yih-Jing Lee ◽  
Xiaoli Dai ◽  
Norma Ojeda ◽  
Hyun Lee ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Pain Sensitivity ◽  
Thermal Hyperalgesia ◽  
Tail Flick ◽  
Protective Effects ◽  
Neonatal Rats ◽  
Astrocyte Activation ◽  
Tail Flick Test ◽  
Painful Sensation ◽  
Cox 2

In this study, we investigated the effects of minocycline, a putative suppressor of microglial activation, on systemic lipopolysaccharide (LPS)-induced spinal cord inflammation, allodynia, and hyperalgesia in neonatal rats. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) or sterile saline was performed in postnatal day 5 (P5) rat pups and minocycline (45 mg/kg) or vehicle (phosphate buffer saline; PBS) was administered (i.p.) 5 min after LPS injection. The von Frey filament and tail-flick tests were performed to determine mechanical allodynia (a painful sensation caused by innocuous stimuli, e.g., light touch) and thermal hyperalgesia (a condition of altered perception of temperature), respectively, and spinal cord inflammation was examined 24 h after the administration of drugs. Systemic LPS administration resulted in a reduction of tactile threshold in the von Frey filament tests and pain response latency in the tail-flick test of neonatal rats. The levels of microglia and astrocyte activation, pro-inflammatory cytokine interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) in the spinal cord of neonatal rats were increased 24 h after the administration of LPS. Treatment with minocycline significantly attenuated LPS-induced allodynia, hyperalgesia, the increase in spinal cord microglia, and astrocyte activation, and elevated levels of IL-1β, COX-2, and PGE2 in neonatal rats. These results suggest that minocycline provides protection against neonatal systemic LPS exposure-induced enhanced pain sensitivity (allodynia and hyperalgesia), and that the protective effects may be associated with its ability to attenuate LPS-induced microglia activation, and the levels of IL-1β, COX-2, and PGE2 in the spinal cord of neonatal rats.

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