Dynamic memory in rodent C-fibres and its impact on spinal nociceptive processing

C-fibre nociceptors display low-level spontaneous firing in the context of tissue injury. Microneurography studies have demonstrated that such low frequency firing can dynamically regulate the activity-dependent slowing (ADS) or temporal pain signal relay of C-fibre nociceptors, thus providing a memory trace of prior activity levels. Here we explore whether low-frequency 'manipulation' can alter C-fibre ADS, in response to subsequent short higher frequency stimulus trains, in compound action potential (CAP) 'population' recordings from isolated rodent dorsal roots of both sexes. In CAP recordings from rat dorsal roots, manipulation (1 Hz, 2 min) increased or decreased ADS in response to short stimulus trains (10 Hz, ×40). This dynamic memory was not sex-dependent. The manipulation-induced change in C-fibre ADS correlated with the level of C-fibre ADS pre-manipulation. In CAP recordings from mouse dorsal roots, manipulation (1 Hz, 1 min) increased C-fibre ADS in response to short stimulus trains (2 Hz, ×40). This dynamic memory was not sex-dependent, despite a more pronounced ADS in males. The impact of dynamic memory on spinal processing was explored through patch-clamp recording of noxious heat responsive neurons with monosynaptic C-fibre inputs in spinal slices. Manipulation (1 Hz, 1 min) increased monosynaptic C-fibre ADS in response to stimulus trains (2 Hz, ×16). This was independent of sex and was associated with synaptic failures. Current-clamp recordings demonstrated that this monosynaptic C-fibre dynamic memory altered action potential firing in noxious heat responsive spinal neurons. In summary, dynamic memory in rodent C-fibres, is not regulated by sex and is communicated to and can alter activity in spinal pain circuits. KEY POINTS: Human studies have previously demonstrated that the peripheral nerve C-fibres, which detect potential tissue-damaging stimuli, are able to retain a memory of prior activity levels that influences their subsequent relay of 'warning' signals. This study demonstrates that this 'memory' is also present in rat and mouse tissue damage-detecting peripheral nerve C-fibres and that this memory is not sex-dependent. We demonstrate that this 'memory' is evident in the C-fibres that directly activate spinal cord neurons responsive to potential tissue damaging heat stimuli and can dynamically regulate their activity. This suggests that ongoing firing of these tissue damage-detecting C-fibres in the context of injury can dynamically regulate how the spinal cord processes pain.