ABSTRACT
The aim of present study was to determine the influence of nitric oxide (NO) synthesis on intrathecal (i.t.) clonidine or baclofen antinociception in the formalin test. Formalin injection into the hindpaw of a rat induces a biphasic response in pain-related behaviours, such that C-fiber activation (acute pain) during phase 1 triggers a state of spinal sensitization characterized by longer lasting phase 2 (tonic pain). Intrathecal clonidine and baclofen, at doses without effect upon motor performance, produced a dose-dependent inhibition of both phases of the formalin test. Potency of both drugs, defined by ID50 for phase 2 of the formalin test, was 3.5 and 0.6 nmol, respectively. Intrathecal coadministration of L-arginine, substrate of NO synthase (NOS) or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently reduced or potentiated, respectively, the antinociceptive effect of clonidine but not that of baclofen in the formalin test. The importance of NO formation in the antinociceptive effect of clonidine is further supported by the observation that neither D-arginine nor D-NAME were able to modify clonidine antinociception. These results suggest that the NO synthesis plays a modulatory role in the antinociceptive effect of clonidine, while the mechanism underlying the baclofen-induced antinociception seems to be different.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Analgesics/pharmacology , Baclofen/pharmacology , Clonidine/pharmacology , GABA Agonists/pharmacology , Nitric Oxide/physiology , Pain Measurement/drug effects , Adrenergic alpha-Agonists/administration & dosage , Analgesics/administration & dosage , Animals , Arginine/pharmacology , Baclofen/administration & dosage , Clonidine/administration & dosage , Enzyme Inhibitors/pharmacology , Formaldehyde , GABA Agonists/administration & dosage , Injections, Spinal , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Postural Balance/drug effects , Rats , Rats, WistarABSTRACT
The anti-emetic effects of ondansetron and droperidol were evaluated in 134 ASA Grade I and II female patients, scheduled for laparoscopic cholecystectomy and minor gynaecological laparoscopic surgery, who were randomly assigned to receive ondansetron 4 mg or droperidol 75 micrograms kg-1 intravenously immediately after induction of anaesthesia. The patients were assessed 1, 6, 12 and 24 h after surgery for intensity of nausea and number of vomiting episodes. In the case of the patients undergoing laparoscopy, vomiting episodes occurred in a similar proportion in patients treated with ondansetron or droperidol, with the probability of the Type I error of 0.05 and the Type error II of 0.1. Although there was no difference between the two groups in emetic episodes following all laparoscopic procedures and gynaecological laparoscopic surgery, there was a significant difference between these parameters after laparoscopic cholecystectomy. The patients treated with ondansetron experienced a lower intensity of nausea (P = 0.04) after laparoscopic cholecystectomy, less frequent severe nausea (P = 0.02) and episodes of vomiting (P = 0.04) when compared with those in the droperidol group. We conclude, that despite the result the droperidol prophylaxis appears to be an effective alternative to ondansetron in all patients undergoing laparoscopy, the ondansetron prophylaxis is superior to droperidol in patients undergoing laparoscopic cholecystectomy.
Subject(s)
Antiemetics/therapeutic use , Cholecystectomy , Droperidol/therapeutic use , Gynecologic Surgical Procedures , Laparoscopy , Ondansetron/therapeutic use , Postoperative Nausea and Vomiting/prevention & control , Adult , Double-Blind Method , Female , Humans , Middle Aged , Prospective StudiesABSTRACT
The inhibition of both phases of the formalin response by intrathecal (IT) clonidine and baclofen, given alone or in combination at a fixed dose ratio, was studied. Both drugs, at doses not affecting motor performance, produced a dose-dependent inhibition of phase 2 of the formalin test. The potency of baclofen and clonidine, defined by their ID50's for phase 2 of the formalin test, was 0.56 and 3.4 nmol, respectively. The combination ID50 of baclofen and clonidine, with the equieffective dose ratio of 1:6, was found to be statistically lower than the theoretical additive ID50. These data suggest that co-administration of alpha2-adrenoceptor or GABA(B) receptor agonists may prove therapeutically useful in treating chronic pain.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Baclofen/pharmacology , Clonidine/pharmacology , GABA Agonists/pharmacology , Pain Threshold/drug effects , Adrenergic alpha-Antagonists/pharmacology , Animals , Drug Interactions , Formaldehyde , Imidazoles/pharmacology , Injections, Spinal , Male , Motor Activity/drug effects , Rats , Rats, WistarABSTRACT
The formalin test, an experimental model of injury-induced central sensitisation, was used. The antinociceptive interaction between intrathecal morphine and clonidine was evaluated based on the inhibition of the phase 1 and 2 of the formalin response, induced by both drugs, given alone or in combinations with fixed dose ratios. Morphine and clonidine, at doses not affecting motor performance, produced dose-dependent inhibition in the formalin test, with similar ID50 values in phase 1 and 2; 0.66 and 0.45 nmol and 4.1 and 3.5 nmol, respectively. Isobolographic analysis revealed a significant synergy. The combination ID50 was found to be significantly lower than the respective theoretical additive ID50 for both fixed dose ratios (1:3 and 1:10) in both phases of the formalin test. The similar total dose fraction of the additive ID50 in phase 1 and 2 indicates the same magnitude of synergy and may suggest that the mechanisms of the spinal clonidine-morphine synergy do not differ significantly between both phases of the formalin test.
