Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat.

Abstract

BACKGROUND:

Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ1 and NMDA receptors, gap junctions and D-amino acid oxidase.

METHODS:

Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (σ1 receptor antagonist), carbenoxolone (a gap junction decoupler), MK-801 (NMDA receptor antagonist) and AS-057278 (inhibitor of D-amino acid oxidase, DAAO) were used to prevent the DMS-induced hypersensitivity, and pregnenolone sulphate (TRPM3 agonist) to recapitulate hypersensitivity.

RESULTS:

DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin.

CONCLUSIONS:

Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the σ1 and NMDA receptors, and DAAO.

• Authors: Hong Wei, Zuyue Chen, Ari Koivisto, Antti Pertovaara
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 73 Issue 2 Pg. 672-679 (Apr 2021) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 33389723 (Publication Type: Journal Article)

Chemical References

• Flavanones
• Flavonoids
• Glucosides
• Isoflavones
• Sphingolipids
• calycosin-7-O-beta-D-glucoside
• naringenin
• N,N-dimethylsphingosine
• Sphingosine
• isosakuranetin

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Flavanones (pharmacology)
• Flavonoids (pharmacology)
• Glucosides (pharmacology)
• Hyperalgesia (physiopathology, prevention & control)
• Isoflavones (pharmacology)
• Male
• Rats
• Rats, Wistar
• Sphingolipids (metabolism)
• Sphingosine (analogs & derivatives, toxicity)
• Spinal Cord (metabolism)