Abstract text (incl. figure legends and references)

Question: Caffeine, a nonselective adenosine receptor antagonist, is the most commonly consumed psycho-stimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid (CSF) secretion and is known both to alleviate and to trigger headache. However, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and pain perception.

Methods: Female Sprague Dawley rats (n=21) were implanted with a novel telemetric device for continuous ICP recordings which allowed for continuously recordings in freely moving rats. Single dose of caffeine (30 or 120 mg/kg i.p.) was given. In a second group (non-implanted), the acute effects of 30mg/kg caffeine on periorbital threshold using Von Frey and spontaneous behavior were utilized using an automated behavioral registration platform (LABORAS) in a randomized cross-over study. Immunofluorescence was performed to localize adenosine receptor (ARs) at choroid plexus (CP).

Results: Single dose of 30 mg/kg caffeine lowered ICP 5h after administration (saline: 0.16±0.9 vs caffeine: -1.18±0.9ΔmmHg, p=0.0098) and lasted up to 11h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP already within 15min (p=0.0018) and lasted up 12h. The periorbital pain thresholds were higher after 1h (saline: 224.6±15.1 vs caffeine: 289.5±8.7 g, p=0.005) and lasted up to 5h. After 5h of administration, the hind paw threshold was higher relative to vehicle (saline: 200.1±7.7 vs caffeine: 245.7±9.1g, p=0.03). Caffeine treated rats had increased locomotor activity, speed and rearing behavior. Expression of A1 was found at CP.

Conclusions: This study demonstrates that caffeine has a lowering effect on ICP as acute treatment and may act on the A1 receptor expressed at CP. Interestingly caffeine caused increased response in cephalic thresholds which was developed in an earlier stage of ICP reduction.