Background and aims: Earlier results have shown that endogenous sphingolipids in the spinal dorsal horn may contribute to pain hypersensitivity induced by peripheral nerve injury. Also, it has been shown in patch clamp recordings performed in cell cultures that sphingolipids can activate transient receptor potential melastatin-3 (TRPM3). TRPM3 is a Ca2+-permeable nonselective cation channel that in the primary afferent terminals is involved in transduction of heat, while the behavioral effect of spinal TRPM3 is still not clear. Here we studied whether spinal TRPM3 is involved in mediating the pain hypersensitivity effect of sphingolipids. Moreover, since sphingolipids have been shown to activate spinal astrocytes, we also assessed effects of drugs acting on spinal astrocyte function on hypersensitivity induced by sphingolipids.

Methods: Experiments were performed in healthy adult male Hannover-Wistar rats with a chronic intrathecal catheter for spinal drug administrations. Pain behavior was assessed with calibrated monofilaments (mechanical nociception) and with Hargreaves’ test (heat nociception). N,N-dimethylsphingosine (DMS) was administered intrathecally (i.t.) to induce pain hypersensitivity. Ononetin, a TRPM3 channel antagonist, was used in attempts to block the effect of spinally administered DMS.

Results: DMS alone produced within 15 min a dose-related (0.05-0.5 μg) mechanical hypersensitivity that lasted at least 24 h. Spinally administered DMS did not influence heat nociception. Preemptive treatment with ononetin (TRPM3 antagonist; 100 μg i.t.) delayed and attenuated development of hypersensitivity, while ononetin failed to reverse established hypersensitivity. Ononetin alone had no effect on pain behavior.

Conclusions：The results are in line with the proposal that spinal TRPM3 and spinal astrocytes contribute to the development of mechanical pain hypersensitivity induced by sphingolipids.

SPINAL TRPM3 IS INVOLVED IN MEDIATING THE HYPERSENSITIVITY EFFECT INDUCED BY SPHINGOLIPIDS IN THE RAT