Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high-threshold afferent inputs in mice.

Chronic pain has reached epidemic proportions worldwide. Despite significant efforts to develop new pharmacologic agents, chronic neuropathic pain remains difficult to treat with current medications [13]. Electrical stimulation of low-threshold afferent Aβ-fibers (Aβ-ES), which mostly signal non-noxious inputs, is used clinically for treating neuropathic pain conditions that are refractory to pharmacotherapy. These therapies include transcutaneous electrical nerve stimulation (TENS), certain forms of peripheral nerve stimulation (PNS), and spinal cord stimulation (SCS), which activates Aβ-fibers in the dorsal column. Neurostimulation therapies provide important alternative strategies for treating chronic pain conditions when other therapies have failed or produce side effects that substantially impair a patient’s quality of life [12,15,45]. The premise behind using Aβ-ES for pain treatment arose from the “gate control” theory, whereby activity of low-threshold afferent fibers triggers pain inhibitory mechanisms in the spinal cord [30]. However, details about the spinal neuronal substrates and cellular mechanisms that underlie pain inhibitory effects of Aβ-ES remain elusive [15,16]. High-threshold afferent fibers (C-, Aδ-fibers) mostly transmit noxious information and terminate principally at superficial (I/II) dorsal horn in the spinal cord. The superficial dorsal horn serves as both a relay station for ascending pain signaling and an important site for integration and modulation of converging nociceptive information. In particular, substantia gelatinosa (SG, lamina II) neurons form important local inter-neuronal circuitry that modulates spinal nociceptive transmission and may be essential for Aβ-ES-induced analgesia [11]. However, it is unclear how Aβ-ES modulates synaptic responses to noxious inputs in superficial dorsal horn. Although previous studies have described different forms (e.g., potentiation, depression) of synaptic plasticity in superficial dorsal horn, the conditioning stimulation used in those studies often requires high intensities that activate high-threshold afferent fibers [29,38,41,42]. To our knowledge, no reports have examined whether conditioning paradigms that use low-threshold Aβ-fiber intensities are capable of inhibiting high-threshold synaptic transmission (presumably nociceptive) in superficial dorsal horn neurons. Therefore, the central effects of Aβ-ES on excitability of SG neurons are largely unknown, especially after nerve injury. Because Aβ-ES pain therapies were shown to be most effective for alleviating chronic pain with a neuropathic origin, animal models of neuropathic pain are particularly suitable for the exploration of mechanisms underlying pain inhibition by Aβ-ES [15,43,46]. Spinal nerve ligation (SNL) is a common rodent model of neuropathic pain and has been used in studies of neurostimulation pain therapies, such as SCS [17,43,52]. By conducting patch-clamp recording in spinal cord slices from naive and SNL mice, we sought to test the hypothesis that certain frequencies of Aβ-ES may attenuate C-fiber–mediated neurotransmission in SG neurons. Since excitatory and inhibitory interneurons play different roles in modulating spinal pain transmission [48], we further examined whether Aβ-ES differentially modulates their excitability in nerve-injured animals by using transgenic mice in which GABAergic inhibitory interneurons and glutamatergic excitatory neuron can be identified by fluorescence for recording. Our findings suggest that activities in Aβ-fibers may induce prolonged depression of synaptic transmission of noxious afferent inputs in SG neurons.