Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters

Abstract

The facet joint is a common source of neck pain, particularly after excessive stretch of its capsular ligament. Peptidergic afferents have been shown to have an important role in the development and maintenance of mechanical hyperalgesia, dysregulated nociceptive signaling, and spinal hyperexcitability that develop after mechanical injury to the facet joint. However, the role of non-peptidergic isolectin-B4 (IB4) cells in mediating joint pain is unknown. Isolectin-B4 saporin (IB4-SAP) was injected into the facet joint to ablate non-peptidergic cells, and the facet joint later underwent a ligament stretch known to induce pain. Behavioral sensitivity, thalamic glutamate transporter expression, and thalamic hyperexcitability were evaluated up to and at day 7. Administering IB4-SAP prior to a painful injury prevented the development of mechanical hyperalgesia that is typically present. Intra-articular IB4-SAP also prevented the upregulation of the glutamate transporters GLT-1 and EAAC1 in the ventral posterolateral nucleus of the thalamus and reduced thalamic neuronal hyperexcitability at day 7. These findings suggest that a painful facet injury induces changes extending to supraspinal structures and that IB4-positive afferents in the facet joint may be critical for the development and maintenance of sensitization in the thalamus after a painful facet joint injury.

Impaired mechanical, heat, and cold nociception in a murine model of genetic TACE/ADAM17 knockdown

“…Despite the normal DRG morphology, the small but significant loss of IB4-positive neurons may suggest that at least a particular subpopulation of small-diameter sensory neurons requires growth regulators that are specifically shed by ADAM17. Even if the decrease in the proportion of nonpeptidergic primary afferent neurons may not appear to be sufficiently large to fully explain the difference in behavior, our finding is in line with previous studies reporting that ablation of IB4-positive neurons transiently reduces both mechanical and heat sensitivity (47, 48).…”

Reshaped Gut Microbial Composition and Functions Associated with the Antifatigue Effect of Salidroside in Exercise Mice

“…[ 38 ] In mice treated with SA, the microbial synthesis of glutamate was inhibited, which may suppress glutamate excitotoxicity and the central sensitization in the central nervous system, indicating the existence of a gut‐brain axis. [ 39 ] Compared with the Ex group, the expression of several enzymes in SA groups were downregulated, namely, NrtA/B/C, nitrate reductase/nitrite oxidoreductase [EC:1.7.5.1; 1.7.99.‐], nitrite reductase (NADH) large subunit [EC:1.7.1.15], cyanate lyase [EC:4.2.1.104], and glutamate dehydrogenase [EC:1.4.1.2], all of which are related to nitrogen metabolism (Figure 8C). Skeletal muscle dysfunction was strongly correlated with the levels of glycogen and glucose.…”

“…[38] In mice treated with SA, the microbial synthesis of glutamate was inhibited, which may suppress glutamate excitotoxicity and the central sensitization in the central nervous system, indicating the existence of a gut-brain axis. [39] Compared with the Ex group, the expression of several enzymes in SA groups were downregulated, namely, NrtA/B/C, nitrate reductase/nitrite oxidoreductase [EC:1. 8C).…”

Toxins as tools: Fingerprinting neuronal pharmacology

“…This approach was used to ablate Neuropeptide Y (NPY) receptor expressing neurons, by conjugating NPY to saporin, which identified an important role for NPY receptor-expressing neurons in mediating anxiety behaviors [114]. Similarly, isolectin B4 (IB4), used to distinguish small-diameter sensory neurons into peptidergic (IB4-negative) and non-peptidergic (IB4positive), is routinely conjugated with saporin to assess the role of non-peptidergic neurons in nociception by targeted chemical removal [179,183]. One intriguing possibility is RIPs…”