Spinal NTS2 receptor activation reverses signs of neuropathic pain

Abstract

Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

“…Our results with the NT receptor antagonist SR142948A and with NTS1/ NTS2 knockout mice also revealed that the analgesic effects of ANG2002 were mediated by both NTS1 and NTS2 receptors. These data reinforce previous findings demonstrating that central delivery of either NTS1 or NTS2 agonists is effective in reducing the mechanical hypersensitivity in the context of neuropathic pain (77,78). It should also be noted that a NT [8][9][10][11][12][13] analog with a cationic non-natural amino acid at position 8, ABS212, has been shown to elicit a sustained analgesic response when administered i.p.…”

Identification of N-[(5-{[(4-Methylphenyl)sulfonyl]amino}-3-(trifluoroacetyl)-1H-indol-1-yl)acetyl]-l-leucine (NTRC-824), a Neurotensin-like Nonpeptide Compound Selective for the Neurotensin Receptor Type 2

“…10,20,21 Coupled with our desire to identify nonpeptide compounds, the lower side effect profile demonstrated by the NTS2 selective peptide 1b prompted us to develop methods of identifying NTS2 selective compounds. 22 …”

Bioactive peptides derived from natural proteins with respect to diversity of their receptors and physiological effects

“…The antinociceptive effect of -lactotensin was blocked by SCH23390, an antagonist of the dopamine D2 receptor suggesting that it was mediated by the D2 receptor downstream of the NTS2 receptor. -Lactotensin has been reported to suppress neuropathic pain [125].…”