Effects of Agmatine on GABAA Receptor Antagonist-induced Tactile Allodynia / 대한통증학회지

BACKGROUND: The intrathecal (IT) GABAA receptor antagonist, bicuculline (BIC), results in tactile allodynia (TA) through disinhibition in the spinal cord. Such disinhibition is considered to be an important mechanism for neuropathic pain. Agmatine, an endogenous polyamine, has a neuro-protective effect in the central nervous system. We investigated the analgesic effects and mechanisms of agmatine action on BIC-induced TA. METHODS: Male Sprague-Dawley rats, weighting 250-300 g, were subjected to implantations of PE-10 into the lumbar subarachnoid space for IT drug injection. Five days after surgery, either 10 microliter of normal saline (NS) or agmatine (30 microgram or 10 microgram) in 10 microliter NS were injected 10 min prior to BIC (10 microgram) or NMDA (5 microgram). We assessed the degree of TA (graded 0: no response, 1: mild response, 2: moderate response, 3: strong response) every 5 min for 30 min. Areas under curves and degree of TA were expressed as mean +/- SEM. Results were analyzed using one-way ANOVA followed by a Tukey test for multiple comparisons. P < 0.05 was considered significant. RESULTS: IT BIC-induced strong TA reached its peak and plateaued between 10 to 15 min. IT NS-NMDA induced mild transient TA for up to 15 min. Preemptive IT AG attenuated IT BIC-induced TA dose dependently and preemptive IT AG10 completely abolished the IT NMDA-induced TA. CONCLUSIONS: Preemptive IT AG attenuated the IT BIC-induced TA through inhibitory actions on postsynaptic NMDA receptor activation. AG might be a viable therapeutic option in the treatment of neuropathic pain.

Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain

Pregabalin binds to the voltage-dependent calcium channel alphadelta subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 & L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED50 of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The alphadeltasubunit might be less involved in the CA in SIP.