Electrophysiologic characterization of the antinociceptive actions of S18616, a novel and potent alpha(2)-adrenoceptor agonist, after acute and persistent pain states.

摘要

[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, [lsqb ]7,8[rsqb ](2-chlorobenzo)-2-amino-1-aza-3-oxa[lsqb ]4,5[rsqb ]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 [mu ]g) 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 [mu ]g). In rats with unilateral spinal nerve (L5-L6) ligation performed 2 weeks before study, S18616 (0.1 to 3.0 [mu ]g) dose-dependently suppressed the C- and A[delta ]-fiber evoked responses and blocked [ldquo ]wind-up[rdquo ] in these neurons. The potency was comparable between nerve-injured and sham-operated rats, and S18616 was equally effective against responsesto 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 [mu ]g) 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. [copy ] 2002 by the American Pain Society