Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats

Spinal noradrenaline (NA) released in response to noxious stimuli may play an important role in suppression of nociceptive transmission. Here, we investigated the efficacy of a competitive NA transporter inhibitor (reboxetine) and a noncompetitive NA transporter inhibitor peptide, Xen2174, isolated from the Pacific cone snail, to treat tactile hypersensitivity following paw incisional surgery. Male Sprague-Dawley rats were anesthetized, an incision of the plantar aspect of the hind paw was performed, and withdrawal threshold to von Frey filaments near the surgical site determined. Reboxetine (0.5-5 μg) and Xen2174 (0.3-100 μg) increased withdrawal threshold when injected 24 h after paw incision, with a peak effect at 15-60 min, for Xen2174, an ED50 value of 0.64 μg. Administration of Xen2174 (3-30 μg) 15 min before incision also reduced hypersensitivity in a dose-dependent manner. Withdrawal threshold after the single 30 μg dose was greater than vehicle control even at 2, 3, and 5 days after incision. Doses ≤30 μg did not alter spontaneous behavior. The anti-hypersensitivity effect of 10 μg of Xen2174 was totally blocked by the α2-adrenoceptor antagonist, idazoxan, and partially blocked by the muscarinic antagonist, atropine. These data suggest that selective NA transporter inhibition suppresses post-incisional hypersensitivity through a different mechanism from that of neuropathic pain, since we previously reported that reversal of hypersensitivity by intrathecal clonidine, an α2-adrenoceptor agonist, following spinal nerve ligation is completely blocked by intrathecal atropine. Finally, these data suggest that intrathecal administration of Xen2174 at the time of spinal anesthesia might produce postoperative analgesia in humans.