| Abstract No.: | B-D2150 |
| Country: | Canada |
| | |
| Title: | ANALGESIA MEDIATED BY ACTIVATION OF A TONIC INHIBITORY CONDUCTANCE IN MURINE SPINAL NEURONS |
| | |
| Authors/Affiliations: | 3 Robert Bonin*; 2 David Eng; 3 John MacDonald; 1 Beverley Orser;
1 University of Toronto, Department of Anesthesiology; 2 University of Toronto, Department of Pharmacology; 3 University of Toronto, Department of Physiology, Toronto, ON, Canada
|
| | |
| Content: | Background: Neuropathic pain is a chronic pain state that often accompanies nerve damage. This type of pain may involve increased excitability of the neuronal circuitry involved in pain sensation. Tonic GABAergic inhibition of spinal neurons can reduce neuronal excitability and may counteract the pathophysiology underlying neuropathic pain. We have identified a tonic GABAergic conductance in spinal cord neurons which is primarily mediated by GABAA receptors containing the δ subunit. The aim of this study was to determine whether potentiation of this tonic conductance can produce analgesia in mice.
Methods: The δGABAA mediated tonic conductance in spinal neurons was studied using electrophysiology. Primary cultures of spinal neurons were obtained from embryonic Swiss White mice and incubated for 14 days. Pain sensitivity and analgesia were tested using the hotplate acute nociception assay at 55°C. Male mice (4-5 months old) were injected with drug or vehicle 30 minutes prior to testing and 15 minutes after baseline performance was measured. The analgesic properties of the interventions were measured as the difference between vehicle and treated latency.
Results: The neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) enhanced the tonic GABA current in cultured spinal neurons but did not activate a tonic current in the absence of GABA. Conversely, the δGABA-A receptor superagonist THIP activated a persistent, bicuculline sensitive current in the absence of GABA. We next tested whether the analgesic properties of these drugs involves the activity of δGABA-A receptors in the spinal cord. Wildtype (WT) and mutant mice lacking the δGABA-A subunit (δ-/-) were injected with low doses of THDOC (6 mg/kg) or THIP (4 mg/kg) i.p. There were no differences between strains following vehicle treatment. THIP increased the latency to hindpaw licking in WT but not δ-/- mice, suggesting that this analgesic activity is dependent on spinal δGABA-A receptors. However, THDOC did not have analgesic activity in either strain of mice at the test dose. A high dose of 20 mg/kg THDOC was also tested without analgesic effect, suggesting that this neuroactive steroid has no analgesic activity in a test of acute pain.
Conclusions: The tonic GABAergic conductance in the spinal cord mediated by δGABA-A receptors can contribute to nociception. The basal activity of these receptors does not appear to regulate acute pain sensation, since vehicle treated WT and δ-/- mice performed similarly in the hotplate test and the potentiation of basal δGABA-A receptor activity with THDOC had no analgesic effect. However, THIP had analgesic activity suggesting that the direct activation of δGABA-A receptors can inhibit pain sensation. One explanation for these findings is that basal GABA activity in the spinal cord is too low for the effective inhibition of pain sensation by tonic inhibition. It is possible that δGABA-A receptor activity regulates pain sensation to a greater degree under conditions of enhanced GABA activity in the spinal cord, which may occur in chronic pain. |
| | |
| Back |
|
