Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain

Abstract

Chronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone-insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail-flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery of NTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCI model), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi- and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post-surgery. CCI-operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28-day testing period. Spinal injection of NT to CCI rats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 μg/kg. Intrathecal administration of the NTS1-selective agonist, PD149163 (30-90 μg/kg) also produced potent anti-allodynic and anti-hyperalgesic effects in nerve-injured rats. Likewise, heat hyperalgesia and tactile allodynia produced by CCI of the sciatic nerve were fully reversed by the NTS1 agonist, NT69L (5-25 μg/kg). Altogether, these results support the idea that the NTS1 receptor subtype is involved in pain modulation, and the potential use of NTS1 agonists for the treatment of painful neuropathies.