Received for publication March 14, 2005.
Revised May 31, 2005.
Accepted for publication May 31, 2005.

Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse

Abstract

Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the 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 CNS pharmacokinetic profile of agmatine remains minimally defined. The present studies determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. Following a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, lumbosacral) tissue and serum were quantified by an isocratic HPLC 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 hours. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than ten minutes following 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. While MK801 inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared to 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 10-30 minutes. Taken collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.

Key words: NMDA, NOS, antihyperalgesia, intrathecal, mice, spinal

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