Increased excitability of medium‐sized dorsal root ganglion neurons by prolonged interleukin‐1β exposure is K + channel dependent and reversible

Key points Neuropathic pain resulting from peripheral nerve injury is initiated and maintained by persistent ectopic activity in primary afferent neurons. Sciatic nerve injury increases the excitability of medium‐sized dorsal root ganglion (DRG) neurons. Levels of the inflammatory cytokine interleukin 1β (IL‐1β) increase and peak after 7 days. Five to six days of exposure of medium sized DRG neurons to 100 p m IL‐1β promotes persistent increases in excitability which abate within 3–4 days of cytokine removal. This is associated with a profound attenuation of K + channel currents but only modest increases in function of cyclic nucleotide‐sensitive hyperpolarization‐activated channels (HCNs) and of voltage‐gated Na + and Ca 2+ channel currents. It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons is capable of initiating an enduring phenotypic shift in their electrophysiological properties that follows sciatic nerve injury. The findings also underline the importance of K + channel modulation in the actions of inflammatory mediators on peripheral neurons.Abstract Chronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the level of interleukin 1β (IL‐1β) in primary afferents that peaks at 7 days. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper‐excitability in sensory nerves, which initiates and maintains chronic neuropathic pain. We have shown previously that 5–6 days of exposure of rat dorsal root ganglia (DRGs) to 100 p m IL‐1β increases the excitability of medium‐sized neurons. We have now found using whole‐cell recording that this increased excitability reverts to control levels within 3–4 days of cytokine removal. The effects of IL‐1β were dominated by changes in K + currents. Thus, the amplitudes of A‐current, delayed rectifier and Ca 2+ ‐sensitive K + currents were reduced by ∼68%, ∼64% and ∼36%, respectively. Effects of IL‐1β on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage‐activated Ca 2+ channel current, a small increase in rates of activation of hyperpolarization‐activated cyclic nucleotide‐gated channel current ( I H ), and a shift in the voltage dependence of activation of tetrodotoxin‐sensitive sodium current (TTX‐S I Na ) to more negative potentials. It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K + channel function and on the continued presence of slightly elevated levels IL‐1β and other cytokines.