Spinal adenosine receptor activation reduces hypersensitivity after surgery by a different mechanism than after nerve injury

Background: Intrathecal adenosine has antinociceptive effects under conditions of hypersensitivity. T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophen) is an allosteric Adenosine Receptor modulator that enhances adenosine binding to the A1 receptor. Intrathecal T62 reduces hypersensitivity to mechanical stimuli in a rat model of neuropathic pain by a circuit that totally relies on activation of alpha2 adrenoceptors. Here, the authors tested whether this same dependence was present in the acute setting of hypersensitivity after surgery.

Methods: Intrathecal catheters were inserted in male Sprague-Dawley rats. An incision of the plantar aspect of the hind paw resulted 24 h later in hypersensitivity, as measured by applying von Frey filaments to the paw. At this time, rats received intrathecal T62, clonidine, or the combination in a blinded, isobolographic design. The effect of the alpha2-adrenoceptor antagonist idazoxan on T62 was also tested.

Results: Intrathecal T62 produced a dose-dependent antihypersensitivity effect, with no effect on ambulation or activity level. Clonidine also produced a dose-dependent antihypersensitivity effect. The ED40 (95% confidence interval) for T62 was 0.77 (0.63-0.91) microg, and that for clonidine was 1.23 (0.56-1.9) microg. Isobolographic analysis indicated synergism between T62 and clonidine. Intrathecal pretreatment with idazoxan only partially inhibited the antihypersensitivity effect of T62.

Conclusions: Intrathecal T62 is effective for postoperative hypersensitivity. The synergy of T62 with clonidine and its only partial antagonism by idazoxan suggest that T62 does not rely entirely on activation of alpha2 adrenoceptors. These results indicate that, after surgery, T62 acts via a mechanism different from that of spinal nerve ligation, a model of chronic neuropathic pain.