Caffeine antinociception in the rat hot-plate and formalin tests and locomotor stimulation: involvement of noradrenergic mechanisms

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Abstract
The present study examined antinociception produced by systemic administration of caffeine in the rat hot-plate (HP) and formalin tests and addressed several aspects of the mechanism of action of caffeine. Locomotor activity was monitored throughout. Caffeine produced a dose-related antinociception the HP (50-100 mg/kg) and formalin tests (12.5-75 mg/kg). When observed during the formalin test, caffeine stimulated locomotor activity between 12.5 and 50 mg/kg; this was followed by a depression in activity at 75 mg/kg. Caffeine did not produce an anti-inflammatory effect as determined by hindpaw plethysmometry, suggesting that antinociception was not secondary to an anti-inflammatory action. Peripheral co-administration of caffeine with the formalin did not produce antinociception, suggesting a predominant central rather than peripheral site of action for caffeine. Naloxone (10 mg/kg) did not reduce the antinociceptive or locomotor stimulant effects of caffeine, suggesting a lack of involvement of endogenous opioids in these actions. Phentolamine (5 mg/kg) enhanced antinociception by caffeine in both the HP and formalin tests, but inhibited locomotor stimulation. Prazosin (0.15 mg/kg) mimicked the action of phentolamine on locomotor stimulation, but idazoxan (0.5 mg/kg) mimicked the action of phentolamine on antinociception in the formalin test. These observations suggest an involvement of different alpha-adrenergic receptors in the two actions of phentolamine. Microinjection of 6-hydroxydopamine (6-OHDA) into the locus coeruleus, which depleted noradrenaline (NA) in the spinal cord and forebrain, inhibited the action of caffeine in the HP test. This was mimicked by intrathecal 6-OHDA which depleted NA in the spinal cord, but not by microinjection of 6-OHDA into the dorsal bundle which depleted NA in the forebrain. These results suggest an integral involvement of noradrenergic mechanisms in the antinociceptive action of caffeine in the HP and formalin tests and in locomotor stimulation, but the nature of this involvement differs for the 3 end points.