Wiley RG, Lappi DA (2011) Selective activation of dorsal horn inhibitory interneurons produces anti-nociception. Neuroscience 2011 Abstracts 804.14. Society for Neuroscience, Washington, DC.
Summary: Intrathecal injections of the excitatory neuropeptide neurotensin are antinociceptive in rats. Lumbar intrathecal injections of the cytotoxic conjugate, neurotensin-saporin (NTS-sap), cause rats to engage in intense scratching, licking and biting of their hindquarters. This observation was interpreted as indicating the rats were experiencing discomfort presumably because NTS-sap selectively destroys nociceptive inhibitory interneurons expressing neurotensin receptors in the superficial dorsal horn of the spinal cord resulting in decreased inhibitory input to nociceptive projection neurons. Based on this finding, we made the excitatory conjugate, neurotensin-cholera toxin A subunit (NTS-CTA) which we hypothesized would tonically activate the same nociceptive inhibitory interneurons and produce anti-nociception/analgesia. Two separate groups of Long Evans hooded female rats were injected, under general anesthesia, with 500 ng of NTS-CTA, produced by Advanced Targeting Systems, San Diego, CA using temporarily positioned subarachnoid catheters which were removed after 15 mins. For the next 72-96 hours, rats showed: 1 – normal spontaneous behavior including grooming, ambulation, defecation and urination; 2 – decreased nocifensive responses on the hotplate at 44C – 47C; 3 – increased hindpaw mechanical withdrawal thresholds; and, 4 – prolonged tail flick response latencies. Systemic naloxone (0.8-2.0 mg/kg, s.c.) did not reverse the anti-nociceptive effect of NT-CTA. Hotplate responses completely returned to baseline within 7 days. These data are interpreted as showing that intrathecal NTS-CTA is reversibly anti-nociceptive by a naloxone-insensitive (non-opioid) mechanism. The likely mechanism of NTS-CTA action is hypothesized to involve tonic activation of NTS receptor-expressing inhibitory interneurons in the superficial dorsal horn of the spinal cord that increases inhibition of nociceptive projection neurons. This strategy may prove useful in treating intractable pain and may be generally useful in the study and manipulation of other populations of inhibitory (or excitatory) interneurons using various neuropeptide-CTA conjugates in such fields as epilepsy, learning and memory, etc. Ongoing work is aimed at identifying the neurons activated by NTS-CTA, testing NTS-CTA in operant pain tests, testing nociceptive effects of other neuropeptide-CTA conjugates and evaluating ways to produce more prolonged activation of the target neurons.