Carlos Paeile

Antinociceptive effects of Ca2+ channel blockers

The antinociceptive action of four Ca2+ channel blockers, nifedipine, nimodipine, verapamil and diltiazem, was evaluated and compared to that of morphine using three algesiometric tests in mice and rats, namely, formalin, writhing and modified hot-plate test. Dose-response curves for all the drugs tested were similar and a significant dose-dependent antinociceptive action was evident in the formalin and writhing tests. However, in the hot-plate test, only nimodipine exhibited a significant analgesic effect, confirming the misleading results previously reported for this test. The findings suggest a pharmacological role of Ca2+ channel blockers in the modulation of antinociception under acute conditions. The analgesic action of Ca2+ channel blockers could be mediated by an increase in the nociceptive threshold resulting from interference with Ca2+ influx at opioid receptors, because Ca2+ influx is critical for the release of neurotransmitters and other substances implicated in nociception and inflammation. It is suggested that if a substance has a Ca2+ channel blocking effect, it should probably have some antinociceptive properties.

Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats

To study the antinociceptive synergy resulting from the combination of opioid receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists on neuropathic pain, an isobolographic analysis of equianalgesic combinations of ketamine with methadone or morphine was performed in rats with mononeuropathy produced by placing four constrictive ligatures around the common sciatic nerve. Two weeks later, the antinociceptive effect of subcutaneous administration of the drugs alone or combined was evaluated by using the paw pressure test. Drugs and their combinations produced dose-dependent antinociception. Combinations produced synergy of a supra-additive nature in the neuropathic paw, but only additive antinociception in the normal paw. The ketamine/methadone combination was more effective to produce antinociception in the neuropathic paw than was the ketamine/morphine association, as revealed by the lower ED25. The results indicate supra-additive synergy between NMDA receptor antagonists and opioids, especially methadone, to produce antinociception in experimental neuropathy.

Synergistic Antinociceptive Effects of Ketamine and Morphine in the Orofacial Capsaicin Test in the Rat

Background The clinical efficacy of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine for treating orofacial pain has already been reported. Side effects related to psychotomimetic disturbances, however, limit ketamine use as an analgesic. Theoretically, this limitation could be minimized by using low doses of ketamine in combination with other analgesics. In the present study, the potential synergistic antinociceptive interaction between ketamine and morphine in the orofacial capsaicin test in rats was investigated. Methods Male Sprague-Dawley rats were subcutaneously injected with solvent, ketamine, morphine, or combination of both drugs. Thirty minutes later, the orofacial capsaicin test was performed by injecting of 1.5 &mgr;g/25 &mgr;l of a capsaicin solution into the vibrissa pad. Animal behavior was recorded on videotape and analyzed off-line. The total time spent on rubbing–scratching nociceptive behavior during a period of 42 min was measured. Results Subcutaneously administered ketamine (0.4, 1.25, 4, 12.5 mg/kg), morphine (0.5, 1, 2, 4 mg/kg) and ketamine + morphine (0.20 + 0.12, 0.40 + 0.24, 0.80 + 0.49, 1.61 + 0.97, 3.21 + 1.94 mg/kg) reduced the rat facial rubbing–scratching behavior in a dose-dependent manner. Isobolographic analysis showed that the ketamine + morphine association inhibited the studied behavior in a superadditive manner. Conclusions These results indicate that ketamine and morphine have antinociceptive effects on the orofacial capsaicin test. Furthermore, their combination produces synergistic antinociception. It is therefore suggested that, used together, ketamine and morphine might be clinically efficient at lower doses than those currently used when administered separately. This could provide a useful strategy for the clinical management of orofacial pain.

Interactions between analgesics and calcium channel blockers

1. The findings, derived from different experimental models, examined in this review, provide evidence that the calcium channel blockers and related drugs possess analgesic effects. 2. The antinociceptive action that some analgesic drugs exhibit may be related to calcium channel blockade. 3. Evidence from a variety of biochemical and pharmacological experimental approaches, support the existence of an interelation between the calcium modulators and the opioid drugs. 4. This idea agrees with the novel neuropharmacological hypothesis that a common very high affinity binding site for multiple neurotransmitters could exist, as has been proposed by Pasternak and Wood (1986). 5. This hypothesis could be extended to the neuromodulators or other neuromediators.

Analgesic action of clonixin, nifedipine and morphine using the formalin test.

1. The analgesic effect of ClX, nifedipine, metamizol, indoprofen and morphine in the pain induced by formalin injection (formalin test) was studied. 2. Attempts to demonstrate tolerance to ClX were unsuccessful. 3. In the analgesic test nifedipine and morphine are approximately 10 times more potent than ClX. 4. The present results suggest that the analgesic action of ClX is not mediated by mu 1, delta or kappa-opioid receptors and the anti-nociceptive effect of nifedipine may be associated with the blockade of the transmembrane inward movements of calcium.

Pre- and postjunctional muscarinic receptor subtypes in the vas deferens of rat.

1. A pharmacological study of the pre- and postjunctional muscarinic receptors of the isolated rat vas deferens was carried out using more selective agonists and antagonists. 2. The prejunctional receptor was characterized on electrically stimulated preparations, while the postjunctional receptor was studied on vasa deferentia without stimulation. 3. The results indicate that atropine exhibited a similar affinity for the two populations of muscarinic receptor subtypes of this tissue. 4. 4-DAMP was able to differentiate with high affinity a subtype located at postjunctional level which had pharmacological similarities with the M3-ACh subtype and with low affinity a subtype located at prejunctional level. 5. The selective M1-ACh agonist McN-A-343 was not able to activate the postjunctional receptor, but showed a similar affinity to ACh for the prejunctional one. 6. At present, the prejunctional receptor can be considered as an atypical M1-ACh subtype based on the results obtained with the selective drugs available.

Ketorolac tromethamine: An experimental study of its analgesic effects in the rat

1. The formalin test and R-III nociceptive electromyographic reflex were used to determine the origin of analgesia induced by ketorolac tromethamine (KT) in rats. 2. The effects of KT and morphine were compared after i.v. administration. 3. Mepacrine and indomethacin were associated to KT to determine if prostaglandins are involved in the central action of KT. 4. In both tests KT had a poor analgesic effect without dose-response relationships. 5. A central component is involved in the analgesia produced by KT, but neither prostaglandins nor opioid receptors seem to mediate this effect.

Antinociceptive effect of clomipramine in monoarthritic rats as revealed by the paw pressure test and the C-fiber-evoked reflex.

The antinociceptive effect of clomipramine was studied in monoarthritic rats by using the paw pressure test and the C-fiber-evoked reflex. Monoarthritis was produced by intra-articular injection of complete Freunds adjuvant into the tibio-tarsal joint. Joint circumference as well as vocalization threshold to graded paw pressure were evaluated weekly during a 14-week period after the intra-articular injection. At week 8, monoarthritic and vehicle-injected control rats were given either clomipramine or saline and both the paw pressure threshold and inhibition of the C-fiber-evoked reflex response were evaluated. Results showed that (i) 1.5, 3.0, and 6.0 mg/kg, i.v. of clomipramine induced significantly greater dose-dependent antinociception to paw pressure testing in the monoarthritic group, as compared to the control one; and (ii) 0.75, 1.5, 3.0, and 6.0 mg/kg, i.v. of clomipramine exerted significantly higher dose-dependent inhibition of the C-reflex activity in monoarthritic rats than in controls. Results suggest that the higher sensitivity to clomipramine in monoarthritic rats could be related to adaptive changes occurring in monoamine metabolism or in other neurotransmitter systems during chronic pain.

Further studies on the understanding of Octodon Degus natural resistance to morphine: A comparative study with the wistar rat

1. Octodon degus shows higher levels of tolerance to morphine when compared with the Wistar rat. 2. In the formalin algesiometric test, this caviomorph is more resistant to pain (P less than 0.01) and to the analgesic effect of morphine (P less than 0.001). 3. CD50 and LD50 were significantly higher in Octodon degus as compared with Wistar rat. 4. Morphine caused in rat severe hypotension, while doses eight times higher in O. degus had a transient effect. 5. 3H-naloxone binding in adrenal glands of O. degus is higher than in other tissue samples assayed from the same animal or rats.

Analgesic and behavioral effects of amphetamine enantiomers, p-methoxyamphetamine and n-alkyl-p-methoxyamphetamine derivatives.

The analgesic effects of (+)- and (-)-amphetamine (AMPH), (+/-)-p-methoxyamphetamine (MA), (+/-)-N-methyl-p-methoxyamphetamine (MMA) and (+/-)-N-ethyl-p-methoxyamphetamine (EMA) were compared using two different algesimetric tests in rats. In the formalin test, (+)-AMPH elicited significant antinociception at doses of 0.2, 2 and 8 mg/kg (i.p.); (-)-AMPH was active at 2 and 8 mg/kg, but not at 0.2 mg/kg; MA elicited very potent and long-lasting antinociception; MMA was less active than MA; EMA showed significant effects only at doses of 2 and 8 mg/kg. In the C-fiber evoked nociceptive reflex assay, i.v. (+)- and (-)-AMPH were ineffective, but the methoxy derivatives showed a similar pattern of action combining inhibitory and excitatory actions. To clarify apparent discrepancies between both algesimetric tests, some behavioral motor performance tests were carried out. These tests confirm the motor stimulatory properties of (+)-AMPH, not shared by the methoxylated amphetamine derivatives. The three methoxy derivatives elicited some stereotypies related to dopaminergic activation such as grooming behavior. (+)-AMPH was also the only drug to increase the acquisition of CARs while MA and EMA were without effect. Avoidance conditioning was seriously impaired in rats injected with MMA. This conditioned behavior can be related to the significant decrease of spontaneous motor activity observed with this drug. In conclusion, the introduction of a para-methoxy group strongly increases the analgesic effects of amphetamine without its stimulatory behavioral effects. The introduction of N-alkyl substituents decreases the analgesic potency of MA.