CAFFEINE ANTINOCICEPTION IN THE RAT HOT-PLATE AND FORMALIN TESTS AND LOCOMOTOR STIMULATION - INVOLVEMENT OF NORADRENERGIC MECHANISMS

The present study examined antinociception produced by systemic admini stration of caffeine in the rat hot-plate (HP) and formalin tests and addressed several aspects of the mechanism of action of caffeine. Loco motor activity was monitored throughout. Caffeine produced a dose-rela ted antinociception the HP (50-100 mg/kg) and formalin tests (12.5-75 mg/kg). When observed during the formalin test, caffeine stimulated lo comotor activity between 12.5 and 50 mg/kg; this was followed by a dep ression in activity at 75 mg/kg. Caffeine did not produce an anti-infl ammatory effect as determined by hindpaw plethysmometry, suggesting th at antinociception was not secondary to an anti-inflammatory action. P eripheral co-administration of caffeine with the formalin did not prod uce antinociception, suggesting a predominant central rather than peri pheral site of action for caffeine. Naloxone (10 mg/kg) did not reduce the antinociceptive or locomotor stimulant effects of caffeine, sugge sting a lack of involvement of endogenous opioids in these actions. Ph entolamine (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 stimulati on, but idazoxan (0.5 mg/kg) mimicked the action of phentolamine on an tinociception in the formalin test. These observations suggest an invo lvement of different alpha-adrenergic receptors in the two actions of phentolamine. Microinjection of 6-hydroxydopamine (6-OHDA) into the lo cus coeruleus, which depleted noradrenaline (NA) in the spinal cord an d 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 deple ted 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 na ture of this involvement differs for the 3 end points.