Low-Threshold Primary Afferent Drive onto GABAergic Interneurons in the Superficial Dorsal Horn of the Mouse

Abstract

Inhibition in the spinal cord dorsal horn is crucial for maintaining separation of touch and pain modalities. Disruption of this inhibition results in allodynia, allowing low-threshold drive onto pain and temperature-sensitive projection neurons. This low-threshold (LT) excitatory pathway is normally under strong inhibition. We hypothesized that superficial dorsal horn inhibitory neurons, which would be ideally located to suppress LT drive onto projection neurons in a feedforward manner, are driven by LT input. In addition, because disinhibition-induced allodynia shares some features with the immature dorsal horn such as elevated sensitivity to LT input, we also questioned whether LT drive onto inhibitory neurons changes during postnatal maturation. To investigate these questions, slices were made at different ages from transgenic mice with enhanced green fluorescent protein expression in GABAergic neurons and whole-cell recordings were made from these fluorescent neurons. Evoked synaptic activity was measured in response to electrical stimulation of the dorsal root. We demonstrate that A␤ fibers activate a significant proportion of superficial dorsal horn GABAergic neurons. This occurs with similar excitatory synaptic drive throughout postnatal maturation, but with a greater prevalence at younger ages. These GABAergic neurons are well situated to contribute to suppressing LT activation of output projection neurons. In addition, the majority of these GABAergic neurons also had convergent input from high-threshold fibers, suggesting that this novel subclass of GABAergic neurons is important for gating innocuous as well as noxious information.

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

“…Dorsal horn functional circuitry is incompletely mapped out, but lamina II GABAergic interneurons are ideally located to gate the flow of nociceptive information from the periphery to supraspinal areas. Previous studies have shown that these interneurons receive both highthreshold and low-threshold primary afferent input (67), and innervate NK1R-expressing projection neurons (21,68), therefore being positioned to provide inhibitory control over dorsal horn nociceptive circuitry. We hypothesize that IL-1β released from microglia or astrocytes rapidly potentiates glycinergic synapses on GABAergic lamina II interneurons that normally inhibit the passage of nociceptive signals to the brain; after inflammation, the nociception-transmitting neurons will in turn be rapidly disinhibited via this mechanism, enhancing the perceived pain and contributing to hyperalgesia and allodynia (44).…”

Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

“…According to the gate control theory (Melzack and Wall, 1965), nociceptive spinothalamic tract neurons are dynamically regulated by inhibition from various sources, including innocuous afferent inputs, which drive interneurons in the superficial dorsal horn (Daniele and MacDermott, 2009). In animals with injured nerves, spinothalamic tract neurons show increased responsiveness to innocuous mechanical stimuli (Palecek et al, 1992).…”

Lamina specific loss of inhibition may lead to distinct neuropathic manifestations: a computational modeling approach

“…(Daniele and MacDermott, 2009). Third, inhibitory neurons of lamina II receive input from both LT and high-threshold (HT) primary afferents (Daniele and MacDermott, 2009), but we considered only the LT drive from Aβ-fibers.…”

“…(Daniele and MacDermott, 2009). Third, inhibitory neurons of lamina II receive input from both LT and high-threshold (HT) primary afferents (Daniele and MacDermott, 2009), but we considered only the LT drive from Aβ-fibers. Fourth, the excitatory central cell reported by Lu and Perl (2005) was assumed to be tonic instead of transient (it actually fires rapidly but briefly to sustained depolarizations).…”

“…As depicted in Figure 1, the Aβ-fiber mediated analgesia is provided by the IC-Neuroid, representing an inhibitory central cell (Zheng et al, 2010), which can be found throughout the lamina II and whose branches often extend to lamina I or III (Yasaka et al, 2010), so it is likely to receive input from Aβ-fibers. However, those inhibitory neurons may also receive inputs from HT primary afferents (Daniele and MacDermott, 2009). Likewise, some of these neurons are more likely to receive inputs from unmyelinated fibers particularly associated to cooling receptors (Zheng et al, 2010).…”