Wiley RG, Lappi DA (2010) Targeting Inhibitory Neurons in the Superficial Dorsal Horn: Neurotensin-Saporin (NTS-SAP) and Neurotensin-Cholera Toxin A Subunit (NTS-CTA) Soc Neurosci Mtg, San Diego CA, Abstract #585.2.
Neurotensin (NTS) and high affinity neurotensin receptors (NTSR-1) are found in the superficial dorsal horn, primarily lamina II. Intrathecal NTS has been reported to be anti-nociceptive, naloxone does not block the anti-nociceptive effects of intrathecal NTS and NTS acting at the NTSR-1 is excitatory. Based on these facts, we hypothesized that intrathecal neurotensin produces anti-nociception by exciting inhibitory interneurons in the superficial dorsal horn. In the present study, we sought to determine the effects, on modified thermal plate responses, of lumbar intrathecal injections of NTS-saporin, that is expected to selectively kill NTSR-1-expressing dorsal horn neurons, and NTS-Cholera toxin A subunit (NTS-CTA), that is expected to excite the same neurons. NTS-sap (200-625 ng) produced sustained, remarkable, vigorous scratching of hindquarters, often to the exclusion of any other activity. 12-15 ng of NTS-sap produced no scratching and increased lick/guard responding on the 44 C hotplate. Lumbar intrathecal injections of NTS-CTA (500 ng) produced profound decrease in lick/guard responding on the 44.5 C hotplate that lasted for 100-150 hours. This unique pattern of effects is consistent with the hypothesis that NTSR-1-expressing lamina II dorsal horn neurons are both inhibitory and anti-nociceptive. These results also are consistent with the intrathecal injections of NTS-CTA producing sustained excitation of these inhibitory interneurons resulting in inhibition of nociceptive projection neurons. This strategy of exciting NTSR-1-expressing inhibitory interneurons of the superficial dorsal horn is a novel approach to achieve non-opioid-mediated analgesia which may prove valuable in treating refractory chronic pain.