Stab-wound injury produced a seven-fold elevation in cyclic adenosine monophosphate (AMP) in mouse brain within one minute. The increase in cyclic AMP in the brain was blocked by prior treatment of the animal by theophylline, chlorpromazine, trifluoperazine hydrochloride, and diphenhydramine hydrochloride. Neither dichloroisoproterenol, pronetalol, nor reserpine blocked in the rise in cyclic AMP concentration due to injury. The results following administration of drugs suggest that the increases in cyclic AMP due to injury may be mediated by adenosine. Theophylline and phenothiazine derivatives have been shown previously to decrease adenosine-mediated increases in cyclic AMP in brain slices. The absence of any effect after administration of dichloroisoproterenol or pronetalol suggests that the increase in cyclic AMP after injury is not through catecholamine release. Hypothermia reduced the increase in cyclic AMP in injured brain after one minute.