Effects of Sciatic Nerve Axotomy on Excitatory Synaptic Transmission

Total length of manuscript (including reference list, figure legends and supplementary figure 14 legends) = 36 pages. ABSTRACT 32 33 Injury or section of a peripheral nerve can promote chronic neuropathic pain. This is initiated by the 34 appearance and persistence of ectopic spontaneous activity in primary afferent neurons that 35 promotes a secondary, enduring increase in excitability of sensory circuits in the spinal dorsal horn 36 ('central sensitization'). We have shown previously that 10-20d of chronic constriction injury (CCI) 37 of rat sciatic nerve produces a characteristic 'electrophysiological signature' or pattern of changes in 38 synaptic excitation of five different electrophysiologically-defined neuronal phenotypes in the 39 substantia gelatinosa of the dorsal horn. Although axotomy and CCI send different signals to the 40 dorsal horn, we now find, using whole-cell recording, that the 'electrophysiological signature' 41 produced 12-22d after sciatic axotomy is quite similar to that seen with CCI. Axotomy thus has 42 little effect on resting membrane potential, rheobase, I-V characteristics or excitability of most 43 neuron types. It does however decrease excitatory synaptic drive to tonic firing neurons and 44 increase that to delay firing neurons. Since many tonic neurons are GABAergic, whereas delay 45 neurons do not contain GABA, axotomy may reduce synaptic excitation of inhibitory neurons 46 whilst increasing that of excitatory neurons. Further analysis of spontaneous and miniature (TTX-47 resistant) EPSC's is consistant with the possibility that decreased excitation of tonic neurons 48 reflects loss of presynaptic contacts. By contrast, increased excitation of 'delay' neurons may reflect 49 increased frequency of discharge of presynaptic action potentials. This would explain how synaptic 50 excitation of tonic cells decreases despite the fact that axotomy increases spontaneous activity in 51 primary afferent neurons. 52 53 3 INTRODUCTION. 54