FIGURE 8.

Proposed mechanisms implying a differential role of the α_2A- and α_2C-adrenoceptors subtypes in pain modulation at the spinal cord level. In general, α₂-adrenoceptors are coupled to G_i/o proteins; thus, when activated, they could promote the inhibition of neurotransmitter release by inhibiting adenylate cyclase activity and inactivating Ca²⁺ channels and/or facilitation of K⁺ currents. Our behavioral and electrophysiological data support the contention that clonidine (a non-selective α_2A/2B/2C-adrenoceptor agonist) induces antinociception via activation of α_2A-adrenoceptors, probably located at presynaptic level (in the primary nociceptive Aδ- and C-fibers), causing a diminution of the WDR cell nociceptive firing. Indeed, α_2A-adrenoceptors activation inhibits tonic (formalin) and acute (electrical) nociceptive input. On the other hand, the selective α_2C-adrenoceptor antagonist, JP 1302, produces per se only behavioral but not electrophysiological antinociception (measured on second WDR cells), suggesting an inhibitory effect on tonic nociception. Since JP 1302-induced antinociception was blocked by bicuculline, a GABAergic mechanism has been resembled. The data could be interpreted as follows: (i) presynaptic activation of α_2A-adrenoceptors by clonidine inhibits acute and tonic peripheral nociception; (ii) the JP 1302-induced antinociception is not mediated by inhibition of the nociceptive primary afferent fibers activity; and (ii) considering that α_2C-adrenoceptors can be found in GABAergic neurons, we could suggest that under a tonic nociceptive stimulus (e.g., inflammatory), activation of α_2C-adrenoceptors play a pronociceptive role. Hence (see Discussion for details), the data support the notion that α_2A-adrenoceptor are mainly localized in primary nociceptive afferent fibers modulating the activity of WDR cells. In contrast, α_2C-adrenoceptors seem to be present in spinal interneurons rather than capsaicin-sensitive fibers modulating second-order nociceptive specific cells.