Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound

doi:10.1016/0014-2999(91)90695-M

European Journal of Pharmacology

Volume 204, Issue 2, 5 November 1991, Pages 121-125

https://doi.org/10.1016/0014-2999(91)90695-M Get rights and content

Abstract

A novel compound, FR64822(N-(4-pyridylcarbamoyl)amino 1,2,3,6,-tetrahydropyridine), displays antinociceptive activities in a variety of assays with mice and rats. It has a strong antinociceptive activity in the acetic acid writhing test (ED₅₀ = 1.8 mg/kg p.o.), whereas it has little antinociceptive activity in the tail flick test. The antinociceptive profile is similar to that of nefopam but different from that of anti-inflammatory agents. The involvement of monoamines in the mechanism of action of FR64822 was investigated. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive activity of FR64822, when tested against acetic acid writhing. A similar reduction of activity was found in mice pretreated with sulpiride (10 mg/kg), a dopamine D₂ receptor antagonist, but not with Sch23390 (0.25 mg/kg), a dopamine D₁ receptor antagonist. Pretreatment with p-chlorophenylalanine, yohimbine and naloxone hardly affected the antinociceptive activity of FR64822. These results were compared with those for nefopam and clonidine. It is suggested that FR64822 induces antinociceptive activity through a novel mechanism of action, indirect stimulation of dopamine D₂ receptors, which differs from that of nefopam in that no specific neurotransmission could be determined in nefopam analgesia.

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For this reason, and in view of the above, Nefopam could be hypothesised to attenuate dyspnoea if TRPV1 was to play a role in its pathogenesis. Of importance, while nefopam also has central effects [20,21] it has no respiratory depressant effect [22]. To test the above hypothesis, we conducted a randomised, double-blind, placebo-controlled, crossover study of nefopam in healthy subjects submitted to experimental dyspnoea of the work/effort type, as induced by inspiratory threshold loading (ITL) and that is highly likely to involve respiratory muscles C-fibres [10].
Dyspnoea is a distressing and debilitating symptom with a major impact on quality of life. Alleviation of dyspnoea therefore constitutes a major clinical challenge. When causative physiological disorders cannot be corrected (“persistent dyspnoea”), nonspecific treatment must be considered. Morphine alleviates dyspnoea but has numerous side-effects including ventilatory depression, which justifies looking for alternatives. Certain forms of dyspnoea involve C-fibres, and can be attenuated by C-fibres blockade. We hypothesised that nefopam, a non-sedative benzoxazocine analgesic known to block the transient receptor potential vanilloid subtype 1 abundantly present on C-fibres, would attenuate dyspnoea.
We conducted a randomised, double-blind, placebo-controlled crossover study of nefopam in healthy subjects submitted to experimental work/effort dyspnoea by inspiratory threshold loading (15 healthy male volunteers; age 23–41). We studied a perceptual outcome (dyspnoea visual analogue scale —D-VAS—) and a neurophysiological outcome (effect of nefopam on dyspnoea-pain counter-irritation as assessed by laser-evoked potentials; an effect of nefopam on dyspnoea was hypothetised to reduce the ability of dyspnoea to inhibit pain). Somaesthetic evoked potentials (SEPs) were studied as a control.
A statistically significant decrease in LEP amplitude was observed in response to loading with nefopam (F = 19.1; p < 0.001) and placebo (F = 5.73 and p < 0.001), with no significant difference between nefopam and placebo and no change in SEP characteristics.
In this study, nefopam did not exhibit any effects on dyspnoea.
Compartmental pharmacokinetics of nefopam during mild hypothermia
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Among the potential pharmacological approaches to inducing hypothermic tolerance is nefopam. Nefopam is a non-opioid, non-steroidal analgesic with spinal and supraspinal sites of action that selectively reduces the shivering threshold (triggering core temperature) without impairing respiration or conciousness.13–19 It is a benzoxazocine compound, structurally related to orphenadrine and diphenhydramine, that inhibits the reuptake of serotonin, norepinephrine, and dopamine20 in an amphetamine-like fashion.18
Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam.
We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling.
A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (se): V₁=24.13 (2.8) litre; V₂=183.34 (13.5) litre; Cl_el=0.54 (0.07) litre min⁻¹; Cl_dist=2.84 (0.42) litre min⁻¹].
The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermia.
Nefopam and ketoprofen synergy in rodent models of antinociception
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This drug (Conway and Mitchell, 1977; Heel et al., 1980) is structurally unrelated to other analgesics and induces antinociception in animals (Biella et al., 2003; Buritova and Besson, 2002; Girard et al., 2001, 2006), and humans (Beloeil et al., 2004; Du Manoir et al., 2003; Guirimand et al., 1999; Heel et al., 1980; Kapfer et al., 2005). Its main mechanism of action involves the inhibition of monoamines reuptake in the central nervous system in vitro (Rosland and Hole, 1990; Tresnak-Rustad and Wood, 1981) and in vivo (Fuller and Snoddy, 1993; Hunskaar et al., 1987; Ohkubo et al., 1991; Vonvoigtlander et al., 1983). It increases the inhibiting tone of serotonergic and norepinephrine descending pathways by inhibiting the synaptosomal uptake of dopamine, norepinephrine and serotonin (Piercey and Schroeder, 1981).
Combinations of analgesics with different mechanisms of action offer the possibility of efficient analgesia with a decrease in side effects as a result of reduced dosages of one or both compounds. Based on a clinical observation of synergism between nefopam, a centrally acting non-opioid that inhibits monoamines reuptake, and ketoprofen, a non-steroidal anti-inflammatory drug, the objective of this study was to further explore this antinociceptive synergy in four distinct animal models of pain (both drugs were administered subcutaneously). Strong antinociceptive properties were observed in the mouse writhing abdominal test with ED₅₀ values of 2.56 ± 0.38 and 1.41 ± 0.41 mg/kg for nefopam and ketoprofen, respectively. In the inflammatory phase of the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind-paw with ED₅₀ of 4.32 ± 0.17 mg/kg for nefopam and 49.56 ± 15.81 mg/kg for ketoprofen. Isobolographic analysis revealed that this drug combination is synergistic in the formalin test and additive in the writhing test. In rat carrageenan-induced tactile allodynia, single administration of nefopam or ketoprofen only partially reduced allodynia. Combination of low analgesic doses of nefopam (10 or 30 mg/kg) with low analgesic doses of ketoprofen (30 or 100 mg/kg) significantly reduced or reversed allodynia, with a more pronounced anti-allodynic effect and a longer duration efficacy. In a rat model of postoperative thermal hyperalgesia induced by incision, co-administration of nefopam at a low analgesic dose (10 mg/kg) with ketoprofen at non-analgesic doses (30 or 100 mg/kg) showed the appearance of a strong anti-hyperalgesic effect, maintained during at least 3 h. In conclusion, co-administration of nefopam with ketoprofen is synergistic, and should allow either to increase their analgesic efficacy and/or to reduce their side effects.
Thermal care in the perioperative period
2008, Best Practice and Research: Clinical Anaesthesiology
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Clinically, this efficacy is manifested as a shivering threshold that is reduced twice as much as the vasoconstriction threshold without a decrease in the gain or maximum intensity of shivering. Nefopam, a benzoxazocine compound is a centrally acting analgesic39,40 with both supra-spinal41,42 and spinal sites of action.43,44 Nefopam does not induce respiratory depression, even in postoperative patients.45
Perioperative hypothermia is a common and serious complication of anesthesia and surgery. Core body temperature, which is normally regulated to within a few tenths of a degree centigrade, can fall by as much as 6 °C during anesthesia. The combination of anesthetic-induced impairment of thermoregulatory control and exposure to a cool operating room environment causes most surgical patients to become hypothermic. Mild intraoperative hypothermia triples the incidence of postoperative wound infections, triples the incidence of postoperative myocardial events and increases perioperative blood loss. Furthermore, it prolongs postoperative recovery and prolongs the duration of action of almost all anesthestic drugs. Effective methods are available for preventing inadvertent perioperative hypothermia. Consequently, it is now routine to maintain intraoperative normothermia.
There is no widely accepted definition for the term ‘mild hypothermia’. Furthermore, the term is not used consistently within the literature. For the purpose of this review, mild hypothermia refers to core temperatures between 34 and 36 °C.
Analysis of the antinociceptive effect of the proanthocyanidin-rich fraction obtained from Croton celtidifolius barks: Evidence for a role of the dopaminergic system
2006, Pharmacology Biochemistry and Behavior
In a previous study, we demonstrated the antinociceptive effect of 63SF, a proanthocyanidin-rich fraction obtained from Croton celtidifolius barks, in chemical and thermal behavioural models of pain in mice. The current study now investigate the possible mechanisms underlying the antinociceptive activity of 63SF in the formalin test, by using drugs which interfere with systems that are implicated in descending control of nociception. The antinociceptive effect of 63SF (11 mg/kg, i.p., given 30 min prior to 2.5% formalin) was not altered by pre-treatment of animals 45–50 min beforehand with either prazosin (α₁-adrenergic antagonist; 0.15 mg/kg, i.p.), yohimbine (α₂-adrenergic antagonist; 0.15 mg/kg, i.p.), ketanserin (5-HT_2A-receptor antagonist; 1.0 mg/kg, i.p.), or l-arginine (substrate for NO synthase, 600 mg/kg, i.p.). On the other hand, treatment with sulpiride, an antagonist of dopaminergic D₂-receptors (1.0 mg/kg, i.p., 45 min of pre-treatment), reversed the antinociceptive activity of 63SF. Pre-treatment of animals with reserpine (5 mg/kg, i.p., 24 h beforehand) did not alter the antinociceptive effect of 63SF. The current results support the view that the 63SF exerts antinociceptive effects by enhancing the activity of descending control, possibly by direct stimulation of dopaminergic D₂ receptors.
Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception
2006, Pharmacological Research
The non-opiate analgesic nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC₅₀): serotonergic 5-HT_2C (1.4 μM), 5-HT_2A (5.1 μM), 5-HT₃ (22.3 μM), 5-HT_1B (41.7 μM), 5-HT_1A (64.9 μM), adrenergic α₁ (15.0 μM) and dopaminergic D₁ (100 μM). Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1–30 mg kg⁻¹) and formalin (1–10 mg kg⁻¹) tests in the mouse. Pretreatments with adrenergic α₁ (prazosin) and α₂ (yohimbine), and serotonergic 5-HT_1B (GR127935) receptor antagonists significantly increased the nefopam ED₅₀ in the writhing test. The serotonergic 5-HT_2C (RS102221) and the dopaminergic D₂ (sulpiride) receptor antagonists inhibited nefopam antinociception in the formalin test. However, in both tests, nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D₁ (SCH23390), serotonergic 5-HT_1A (NAN-190, WAY100635), 5-HT_2A (R96544, ketanserin), 5-HT₃ (tropisetron), and 5-HT₄ (SDZ205557). In conclusion, nefopam analgesic activity could be modulated by the adrenergic α₁ and α₂ receptors, the dopaminergic D₂ receptors, and the serotonergic 5-HT_1B and 5-HT_2C receptor subtypes.

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Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound

Abstract

Eur. J. Pharmacol.

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Eur. J. Pharmacol.

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Brain Res.

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