Cav3 channels play an important role in modulating chronic pain. However, less is known about the functional changes of Cav3 channels in superficial spinal dorsal horn in neuropathic pain states. Here, we examined the effect of partial sciatic nerve ligation (PSNL) on either expression or electrophysiological properties of Cav3 channels in superficial spinal dorsal horn. Our in vivo studies showed that the blockers of Cav3 channels robustly alleviated PSNL-induced mechanical allodynia and thermal hyperalgesia, which lasted at least 14 days following PSNL. Meanwhile, PSNL triggered an increase in both mRNA and protein levels of Cav3.2 but not Cav3.1 or Cav3.3 in rats. However, in Cav3.2 knockout mice, PSNL predominantly attenuated mechanical allodynia but not thermal hyperalgesia. In addition, the results of whole-cell patch-clamp recordings showed that both the overall proportion of Cav3 current-expressing neurons and the Cav3 current density in individual neurons were elevated in spinal lamina II neurons from PSNL rats, which could not be recapitulated in Cav3.2 knockout mice. Altogether, our findings reveal that the elevated functional Cav3.2 channels in superficial spinal dorsal horn may contribute to the mechanical allodynia in PSNL-induced neuropathic pain model.

Spinal lamina II (substantia gelatinosa, SG) neurons integrate nociceptive information from the primary afferents and are classified according to electrophysiological (tonic firing, delayed firing, single spike, initial burst, phasic firing, gap firing and reluctant firing) or morphological (islet, central, vertical, radial and unclassified) criteria. T-type calcium (Cav3) channels play an essential role in the central mechanism of pathological pain, but the electrophysiological properties and the cell-type specific distribution of T-type channels in SG neurons have not been fully elucidated. To investigate the electrophysiological and morphological features of T-type channel-expressing or -lacking neurons, voltage- and current-clamp recordings were performed on either transverse or parasagittal spinal cord slices. Recording made in transverse spinal cord slices showed that an inward current (IT) was observed in 44.5% of the SG neurons that was fully blocked by Ni2+ and TTA-A2. The amplitude of IT depended on the magnitude and the duration of hyperpolarization pre-pulse. The voltage for eliciting and maximizing IT were −70 mV and −35 mV, respectively. In addition, we found that most of the IT-expressing neurons are tonic firing neurons and exhibit more negative action potential (AP) threshold and smaller difference of AP threshold and resting membrane potential (RMP) than those neurons lacking IT. Consistently, a specific T-type calcium channel blocker TTA-P2 increased the AP threshold and enlarged the difference between AP threshold and membrane potential (Ihold = 0). Meanwhile, the morphological analysis indicated that most of the IT-expressing neurons are islet neurons. In conclusion, we identify a cell-type specific distribution and the function of T-type channels in SG neurons. These findings might provide new insights into the mechanisms underlying the contribution of T-type channels in sensory transmission.

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The tumor suppressor p53 plays a crucial role in embryonic neuron development and neurite growth, and its involvement in neuronal homeostasis has been proposed. To better understand how the lack of the p53 gene function affects neuronal activity, spine development, and plasticity, we examined the electrophysiological and morphological properties of layer 5 (L5) pyramidal neurons in the primary somatosensory cortex barrel field (S1BF) by using in vitro whole-cell patch clamp and in vivo two-photon imaging techniques in p53 knockout (KO) mice. We found that the spiking frequency, excitatory inputs, and sag ratio were decreased in L5 pyramidal neurons of p53KO mice. In addition, both in vitro and in vivo morphological analyses demonstrated that dendritic spine density in the apical tuft is decreased in L5 pyramidal neurons of p53KO mice. Furthermore, chronic imaging showed that p53 deletion decreased dendritic spine turnover in steady-state conditions, and prevented the increase in spine turnover associated with whisker stimulation seen in wildtype mice. In addition, the sensitivity of whisker-dependent texture discrimination was impaired in p53KO mice compared with wildtype controls. Together, these results suggest that p53 plays an important role in regulating synaptic plasticity by reducing neuronal excitability and the number of excitatory synapses in S1BF.

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Background and Purpose Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental Approach Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key Results Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (NaV1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice. Conclusion and Implications The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.