Abstract

Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. After a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered agmatine. The pharmacodynamic response to agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.