Nefopam and ketoprofen synergy in rodent models of antinociception.

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.

Efficacy of moclobemide in a rat model of neurotoxicant-induced edema.

The potent antidepressant effect of moclobemide, a selective and reversible type A monoamine oxidase (MAO) inhibitor, is clinically established. In view of the ongoing debate on the neuroprotective properties of MAO inhibitors, the present study was undertaken to further define the protective effect of moclobemide in a rat model of neurotoxicant-induced edema. In this model, daily oral triethyltin (TET) administration for 5 consecutive days strongly perturbed the rat behaviour and induced a cerebral edema at the 5th day. Oral coadministration of moclobemide (2 x 100 mg.kg-1.day-1) with TET blocked the development of brain edema and the increase in the cerebral chloride content induced by TET. Moreover, moclobemide reduced the increase in the cerebral sodium content and attenuated the neurological deficit. In conclusion, moclobemide possesses potent protective properties in this rat model of cerebral edema, suggesting potential clinical utility as a neuroprotectant.

Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception.

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 (IC(50)): serotonergic 5-HT(2C) (1.4 microM), 5-HT(2A) (5.1 microM), 5-HT(3) (22.3 microM), 5-HT(1B) (41.7 microM), 5-HT(1A) (64.9 microM), adrenergic alpha(1) (15.0 microM) and dopaminergic D(1) (100 microM). 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 alpha(1) (prazosin) and alpha(2) (yohimbine), and serotonergic 5-HT(1B) (GR127935) receptor antagonists significantly increased the nefopam ED(50) in the writhing test. The serotonergic 5-HT(2C) (RS102221) and the dopaminergic D(2) (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 D(1) (SCH23390), serotonergic 5-HT(1A) (NAN-190, WAY100635), 5-HT(2A) (R96544, ketanserin), 5-HT(3) (tropisetron), and 5-HT(4) (SDZ205557). In conclusion, nefopam analgesic activity could be modulated by the adrenergic alpha(1) and alpha(2) receptors, the dopaminergic D(2) receptors, and the serotonergic 5-HT(1B) and 5-HT(2C) receptor subtypes.

Role of the histamine system in nefopam-induced antinociception in mice.

The present study explored the role of the histaminergic system in nefopam analgesia based on the structural relationship between nefopam and diphenhydramine. In vitro binding assays revealed that nefopam possesses moderate affinity for histamine H1 and H2 receptor subtypes, with IC50 of 0.8 and 6.9 microM, respectively, but no affinity for histamine H(3) receptor subtype until 100 microM. Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1-30 mg/kg) and formalin (1-10 mg/kg) tests in the mouse. Pretreatment with the histamine-depleting agent alpha-fluoromethylhistidine (alpha-FMH, 50 mg/kg), the histamine H1 receptor antagonist pyrilamine (3 or 10 mg/kg), or the histamine H2 receptor antagonists cimetidine (100 mg/kg) and zolantidine (10 or 30 mg/kg) did not significantly modify nefopam antinociception in both tests. The histamine H3 receptor agonist R(-)alpha-methylhistamine (RAMH, 10 mg/kg) did not significantly modify the nefopam analgesic activity in the writhing test. At 25 mg/kg, RAMH inhibited nefopam antinociception at 3 mg/kg, but not at 10 mg/kg in the formalin test. However, pretreatment with the histamine H3 receptor antagonist thioperamide (25 mg/kg) inhibited nefopam antinociception in the writhing test, but not in the formalin test. In conclusion, nefopam analgesic activity is not mediated by histamine H1 or H2 receptors, but can be slightly modulated by histamine H3 receptors in mouse pain tests.