Pharmacological switch in Aβ-fiber stimulation-induced spinal transmission in mice with partial sciatic nerve injury

Background: We have previously demonstrated that different spinal transmissions are involved in the nociceptive behavior caused by electrical stimulation of A beta-, A delta- or C-fibers using a Neurometer (R) in naive mice. In this study, we attempted to pharmacologically characterize the alteration in spinal transmission induced by partial sciatic nerve injury in terms of nociceptive behavior and phosphorylation of extracellular signal-regulated kinase (pERK) in the spinal dorsal horn. Results: A beta-fiber responses (2000-Hz), which were selectively blocked by the AMPA/kainate antagonist CNQX in naive mice, were hypersensitized but blocked by the NMDA receptor antagonists MK-801 and AP-5 in injured mice in an electrical stimulation-induced paw withdrawal (EPW) test. Although Ad- fiber responses (250-Hz) were also hypersensitized by nerve injury, there was no change in the pharmacological characteristics of Ad- fiber responses through NMDA receptors. On the contrary, C-fiber responses (5-Hz) were hyposensitized by nerve injury. Moreover, A delta- and C-, but not A beta-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horns of naive mice, and corresponding antagonists used in the EPW test inhibited this increase. In mice with nerve injury, A beta- as well as Ad- fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horn, whereas C- fiber stimulation decreased this number. The nerve injury-specific pERK increase induced by A beta-stimulation was inhibited by MK-801 and AP-5, but not by CNQX. However, A beta- and Ad- stimulations did not affect the number or size of pERK-positive neurons in the dorsal root ganglion, whereas C-fiber-stimulation selectively decreased the number of pERKpositive neurons. Conclusion: These results suggest that A beta- fiber perception is newly transmitted to spinal neurons, which originally receive only A delta- and C- fiber-mediated pain transmission, through NMDA receptor-mediated mechanisms, in animals with nerve injury. This pharmacological switch in A beta-fiber spinal transmission could be a mechanism underlying neuropathic allodynia.