Antinociceptive and morphine modulatory actions of spinal orphanin FQ

1998 ◽  
Vol 76 (3) ◽  
pp. 314-324 ◽  
Author(s):  
K H Jhamandas ◽  
M Sutak ◽  
G Henderson
Keyword(s):  
Opioid Receptor ◽  
Dose Range ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Tail Flick ◽  
Orphanin Fq ◽  
Cross Tolerance ◽  
Indwelling Catheters ◽  
Antinociceptive Effects ◽  
Pressure Tests

Orphanin FQ (nociceptin, OFQ), a heptadecapeptide peptide, has been designated as an endogenous ligand at the orphan receptor ORL1, which lacks affinity for opioid receptor ligands. OFQ-like immunoreactivity has been localized in spinal cord areas that are involved in the processing of nociceptive signals. In this study, the effects of spinally administered OFQ on thermal and mechanical nociceptive stimuli were investigated following intrathecal (i.t.) injection in unanesthetized rats bearing chronic indwelling catheters in the subarachnoid space. Intrathecal OFQ produced two distinct acute actions: an opioid-like antinociceptive effect, and antagonism of morphine-induced antinociception. Chronic administration produces tolerance. Acute actions were as follows. First, injection of OFQ alone in the dose range 10-100 nmol produced sustained antinociceptive effects in the tail-flick (baseline latency 1.5-2 s) and paw-pressure tests. These effects peaked at 45-60 min post-injection, were fully reversible, and were observed in absence of discernable motor impairments. Intrathecal naloxone (5 nmol) significantly attenuated the antinociceptive effects of OFQ (50 nmol i.t.) in tail-flick and paw-pressure tests. A 24-h pretreatment with the irreversible opioid receptor antagonist, beta -flunatrexamine (2 nmol i.t.), also attenuated the antinociceptive effects of OFQ (50, 100 nmol i.t.) and of morphine (7.5 nmol i.t.) in both tests. Low doses (1, 5 nmol) of OFQ, which failed to produce antinociception in the tail-flick test involving a baseline latency of 1.5-2 s, produced a strong antinociceptive response when the baseline latency was increased to 5-6 s. Second, intrathecal OFQ, at doses (0.5, 1.0, and 5.0 nmol) that had no antinociceptive activity in the tail-flick (baseline latency 1.5-2 s) and paw-pressure tests, attenuated the antinociceptive effect of morphine (7.5 nmol i.t.) in these tests. However, a threshold OFQ dose (10 nmol) significantly extended the duration of antinociception induced by morphine (7.5 nmol i.t.) or deltorphin (20 nmol i.t.). Chronic actions were as follows. In rats that were rendered tolerant to spinal morphine, by a continuous intrathecal infusion (7.5 nmol/h) of the agonist for 5 days, the OFQ dose-response curves for its antinociceptive effect in the tail-flick and paw-pressure tests were significantly shifted to the right. In separate experiments, repeated intrathecal injection of OFQ (50 nmol) or morphine (7.5 nmol) produced a significant decline in their antinociceptive effects. Thus, intrathecally administered OFQ produces both development of tolerance to its antinociceptive actions and cross-tolerance to the action of morphine.Key words: orphanin FQ, nociceptin, spinal antinociception, opioid antagonism, tolerance, cross-tolerance.

scholarly journals Comparison of antinociceptive effect of the antiepileptic drug gabapentin to that of various dosage combinations of gabapentin with lamotrigine and topiramate in mice and rats

2011 ◽  
Vol 02 (02) ◽  
pp. 130-136 ◽  
Author(s):  
Keshab Raj Paudel ◽  
SK Bhattacharya ◽  
GP Rauniar ◽  
BP Das
Keyword(s):  
Pain Perception ◽  
Late Phase ◽  
Antinociceptive Effect ◽  
Experimental Pain ◽  
Mechanical Hyperalgesia ◽  
Tail Flick ◽  
Hot Plate ◽  
Analgesic Effects ◽  
Pain Models ◽  
Antinociceptive Effects

ABSTRACT Introduction: Newer anticonvulsants have a neuromodulatory effect on pain perception mechanisms in a hyperexcitable and damaged nervous system. Aim: This study was designed to study the analgesic effects of gabapentin alone and in combination with lamotrigine and topiramate in experimental pain models. Materials and Methods: Adult albino mice (n = 490) weighing 20–30 g and rats (n = 130) weighing 100–200 g were injected intraperitoneally with gabapentin, lamotrigine, and topiramate alone and in different dose combinations. The hot-plate method, tail-flick method, capsaicin-induced mechanical hyperalgesia, and formalin assay were used to assess the antinociceptive effects. Results: Of the three antiepileptic drugs, when given separately, gabapentin was more efficacious than either topiramate or lamotrigine in all the pain models. Combination of 25 mg/kg gabapentin with 25 mg/kg topiramate was more efficacious (P <.05) than 50 mg/kg gabapentin alone in the capsaicin-induced mechanical hyperalgesia test. Similarly, 50 mg/kg gabapentin with 50 mg/kg topiramate or 5 mg/kg lamotrigine was more efficacious (P <.05) than 50 or 100 mg/kg gabapentin alone in late-phase formalin-induced behaviors. Conclusions: Combination of gabapentin with either lamotrigine or topiramate produced better results than gabapentin alone in capsaicin-induced mechanical hyperalgesia test and in late-phase formalin-induced behaviors.

The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception

2013 ◽  
Vol 4 (4) ◽  
pp. 259-259
Author(s):  
Viljami Jokinen ◽  
Tuomas O. Lilius ◽  
Mikko S. Neuvonen ◽  
Antti J. Väänänen ◽  
Mikko O. Niemi ◽  
...  
Keyword(s):  
Antinociceptive Effect ◽  
Morphine Tolerance ◽  
Tail Flick ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Mineralocorticoid Receptor Antagonist ◽  
P Glycoprotein ◽  
Antinociceptive Effects ◽  
The Brain ◽  
Glycoprotein Inhibition

Abstract Aims Spironolactone, an antimineralocorticoid, has been reported to potentiate the cataleptic effect of morphine in the rat. Since no previous research exists on the matter and the interaction might be clinically significant, the effects of spironolactone on morphine antinociception and pharmacokinetics in the rat were investigated. Methods Male SD rats were used to assess the effects of spironolactone on acute morphine-induced antinociception, development of morphine tolerance, and established morphine tolerance in the tail-flick and hot plate tests. Spironolactone was also administered with loperamide to assess whether spironolactone enhances the brain distribution of the acknowledged P-glycoprotein substrate across the blood-brain barrier. Results Spironolactone had no antinociceptive effects of its own but when co-administrated with morphine the antinociceptive effect of morphine was greatly enhanced. Morphine concentrations in the brain were increased fourfold in the spironolactone co-administrated group. Spironolactone did not inhibit the formation of pro-nociceptive morphine-3-glucuronide, nor did inhibit the development of tolerance. The peripherally restricted opioid, loperamide, had no antinociceptive effects by itself, but co-administration with spironolactone produced a clear change in the hot plate test. Conclusions Although mineralocorticoids have been proposed to take part in pain signaling, in our setting spironolactone did not have antinociceptive properties of its own. The increased antinociceptive effect of morphine is apparently caused by the increased morphine brain concentrations. We suggest this to be due to P-glycoprotein inhibition, as indicated by the loperamide assay. The clinical relevance of P-glycoprotein inhibition by spironolactone should be studied.

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 Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1370 ◽  
Author(s):  
Ferenc Zádor ◽  
Amir Mohammadzadeh ◽  
Mihály Balogh ◽  
Zoltán S. Zádori ◽  
Kornél Király ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Antinociceptive Effect ◽  
Gastrointestinal Transit ◽  
Inhibitory Effect ◽  
In Vitro Tests ◽  
Tail Flick ◽  
The Novel ◽  
Gastrointestinal Side Effects

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Antinociceptive effects of intrathecally administered human β-endorphin in the rat and cat

1978 ◽  
Vol 56 (5) ◽  
pp. 754-759 ◽  
Author(s):  
Tony L. Yaksh ◽  
James L. Henry
Keyword(s):  
Subarachnoid Space ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Opiate Receptor ◽  
Tail Flick ◽  
Dose Ratio ◽  
Response Curves ◽  
Indwelling Catheter ◽  
Spinal Subarachnoid Space

Rats chronically implanted with intrathecal catheters displayed a dose-dependent increase in the hot-plate and tail-flick response latencies following the injection of human β-endorphin into the lumbar spinal subarachnoid space through the indwelling catheter. β-Endorphin was approximately 25 times more potent than morphine on a molar basis. Matching morphine and β-endorphin doses such that approximately equal submaximal effects occurred, it was observed that the antinociception produced by β-endorphin lasted approximately three times longer than that produced by morphine. Experiments with intrathecal injection of β-endorphin into the spinal subarachnoid space of cats fitted with intrathecal catheters also revealed a potent antinociceptive effect which was completely antagonized by naloxone. In the rats, naloxone administered systemically in doses of 10–100 μg/kg produced a parallel shift in the dose–response curves of both nociceptive measures suggesting a competitive antagonism. Using a dose ratio analysis, an in vivo pA2 of 7.1 for naloxone was obtained. These data and those derived from previous work based on the pA2 suggest that the interaction of morphine, certain pentapeptides, and β-endorphin is the same with regard to the spinal opiate receptor population mediating behavioraily defined analgesia.

Lack of cross-tolerance between the antinociceptive effect of intrathecal orphanin FQ and morphine in the rat

1997 ◽  
Vol 223 (1) ◽  
pp. 49-52 ◽  
Author(s):  
Jing-Xia Hao ◽  
Zsuzsanna Wiesenfeld-Hallin ◽  
Xiao-Jun Xu
Keyword(s):  
Antinociceptive Effect ◽  
Orphanin Fq ◽  
Cross Tolerance

Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

1996 ◽  
Vol 84 (4) ◽  
pp. 873-881. ◽  
Author(s):  
Tian-Zhi Guo ◽  
Jian-Yu Jiang ◽  
Ann E. Buttermann ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Pertussis Toxin ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Locus Ceruleus ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Latency ◽  
Pharmacologically Active ◽  
Sites Of Action

Background Alpha(2)-Adrenergic agonists such as clonidine and dexmedetomidine are known to produce sedation and analgesia in humans. The sedative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rats. While the antinociceptive response to alpha(2) agonists, given intrathecally, is mediated predominantly in the spinal cord, other sites of action have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive effect. Methods For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats. Dexmedetomidine (3.5 micrograms/0.2 microliter) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injecton (50 micrograms/kg). The antinociceptive effect of dexmedetomidine was measured using the tail-flick latency response. To determine the sites through which dexmedetomidine injection into the LC produces antinociception, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,066 and pertussis toxin administered either into the LC or intrathecally before injection of dexmedetomidine systemically or directly into the LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional characteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intrathecal) were studied. Results Dexmedetomidine placed into the LC produces a dose-dependent increase in the tail-flick latency. This antinociceptive effect was blocked by pertussis toxin and by the alpha(2) antagonists atipamezole and L659,066 placed in the LC. Intrathecal administration of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. (3)H-dexmedetomidine introduced into the LC did not reach the spinal cord in pharmacologically active concentrations; also, intrathecally administered (3)H-atipamezole did not reach the LC in appreciable amounts. The systemic administration of dexmedetomidine produced an increase in tail-flick latency, and this effect was attenuated by the injection of atipamezole and L659,066 into the LC. Conclusions Part of the mechanism by which dexmedetomidine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produced by injection of this drug into the LC can be blocked by specific alpha(2) antagonists injected into the LC. Furthermore, the action of dexmedetomidine in the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinociceptive effect of LC dexmedetomidine injection also can be blocked by intrathecal injection of antipamezole and pertussis toxin.

scholarly journals Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Renata Cristina Mendes Ferreira ◽  
Ana Flávia Almeida-Santos ◽  
Igor Dimitri Gama Duarte ◽  
Daniele C. Aguiar ◽  
Fabricio A. Moreira ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Antinociceptive Effect ◽  
Opioid System ◽  
Prostaglandin E ◽  
Intraplantar Injection ◽  
Opioid Receptor Antagonist ◽  
Antinociceptive Effects ◽  
The Right

Background. Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect.Methods. Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2, 2 μg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2injection.Results. Aripiprazole (100 μg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 μg/paw), a nonselective opioid receptor antagonist. The role ofμ-,δ-, andκ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 μg/paw), naltrindole (15, 30, and 60 μg/paw), and nor-binaltorphimine (200 μg/paw), respectively. The data indicated that only theδ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 μg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 μg/paw) aripiprazole-induced peripheral antinociception.Conclusion. The results suggest the participation of the opioid system viaδ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.

Sign in / Sign up

Export Citation Format

Share Document