Cannabinoid receptor-1 inhibition causes anesthetic-induced excitation in septic rats

In systemic inflammation and sepsis, the endo-cannabinoid system is upregulated [1]. While it is known that neuronal cannabinoid signalling via cannabinoid receptor-1 (CB1) in the central nervous system represents an intrinsic neuroprotective response [2] and exerts anti-epileptic activity [3], inhibition of CB1 (CB1inh) has been suggested as an experimental target for sepsis therapy [4]. We studied the effects of CB1inh in rats with experimental sepsis during anesthesia induction with pentobarbital.

Five groups of Lewis rats were included in the study: Group 1 - sham-operated controls treated with CB1inh (AM281, 2.5 mg/kg i.v., n = 12), Group 2 - animals with colon ascendens stent peritonitis (CASP)-induced sepsis treated with CB1inh (n = 12). As additional control groups we administered in CASP animals the CB1 agonist ACEA (2.5 mg/kg i.v.; Group 3; n = 4) or the solvent DMSO (Group 4; n = 4). In Group 5 we administered 50 mg/kg ketamine for induction of anesthesia 14 hours following the CASP treated by CB1inh. All other groups received a standard dose of pentobarbital (40 mg/kg i.v.) 14 hours following CASP procedure.

In five out of 12 septic animals (42%) with CB1inh (Group 2) we observed tonic-clonic seizures immediately after induction of anesthesia with a standard dose of pentobarbital. In sham-operated animals (Group 1) or CASP animals without CB1inh (Group 4) we did not observe anesthetic-induced excitation. Replacement of the barbiturate by ketamine (Group 5) avoided seizures as well as treatment with the CB1 agonist (Group 3).

CB1 inhibition in sepsis may increase the incidence of anesthetic-induced excitation and reduce CB1-mediated intrinsic neuroprotective response.