Electrophysiologic characterization of the antinociceptive actions of S18616, a novel and potent alpha 2-adrenoceptor agonist, after acute and persistent pain states.
alpha (2)-Adrenoceptor (AR) agonists are active in behavioral models of persistent pain involving tissue and nerve damage. We evaluated the spinal effect of a novel, potent, and selective alpha (2)-AR agonist, [7,8](2-chlorobenzo)-2-amino-1-aza-3-oxa[4,5]spirodeca-1,7-diene (S18616), on the responses of dorsal horn neurons in halothane-anesthetized rats. Intrathecal administration of S18616 (0.1 to 3.0 microg) dose-dependently suppressed C- and A delta-fiber evoked responses but not the A beta-fiber evoked response. Drug effects were reversed by the alpha (2)-AR antagonists, atipamezole and idazoxan (100 microg). In rats with unilateral spinal nerve (L5-L6) ligation performed 2 weeks before study, S18616 (0.1 to 3.0 microg) dose-dependently suppressed the C- and A delta-fiber evoked responses and blocked "wind-up" in these neurons. The potency was comparable between nerve-injured and sham-operated rats, and S18616 was equally effective against responses to thermal and high-intensity mechanical stimuli. Interestingly, the effectiveness of S18616 on the low-intensity mechanical evoked response was significantly enhanced after nerve injury. Finally, S18616 (0.3 and 3.0 microg) reduced the neuronal responses produced by intraplantar injection of formalin. In conclusion, S18616 dose-dependently and potently inhibits the responses of dorsal horn neurons to peripheral stimulation in normal, inflamed, and neuropathic rats. These data support the use of spinal S18616 and other alpha (2)-AR agonists in the management of clinical pain.
Suzuki
Rie
R
Department of Pharmacology, University College London, UK. ucklrsu@ucl.ac.uk
Green
G Mark
GM
Millan
Mark J
MJ
Dickenson
Anthony H
AH