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Effects of Intrathecal SNC80, a Delta Receptor Ligand, on Nociceptive Threshold and Dorsal Horn Substance P Release

2013; American Society for Pharmacology and Experimental Therapeutics; Volume: 347; Issue: 2 Linguagem: Inglês

10.1124/jpet.113.206573

1521-0103

Milad Kouchek, Toshifumi Takasusuki, Tetsuji Terashima, Tony L. Yaksh, Qinghao Xu,

Pain Management and Placebo Effect

Delta-opioid receptors (DOR) are present in the superficial dorsal horn and are believed to regulate the release of small afferent transmitters as evidenced by the effects of spinally delivered delta-opioid preferring peptides. Here we examined the effects of intrathecal SNC80 [(+)-4-[ α ( R )- α -[(2 S ,5 R )-4-allyl-2,5-dimethyl-1-piperazinyl]-3-(methoxybenzyl)- N,N -diethylbenzamide], a selective nonpeptidic DOR agonist, in three preclinical pain models, acute thermal escape, intraplantar carrageenan-tactile allodynia, and intraplantar formalin flinches, and on the evoked release of substance P (SP) from small primary afferents. Rats with chronic intrathecal catheters received intrathecal vehicle or SNC80 (100 or 200 μ g). Intrathecal SNC80 did not change acute thermal latencies or carrageenan-induced thermal hyperalgesia. However, SNC80 attenuated carrageenan-induced tactile allodynia and significantly reduced both phase 1 and phase 2 formalin-induced paw flinches, as assessed by an automatic flinch counting device. These effects were abolished by naltrindole (3 mg/kg i.p.), a selective DOR antagonist, but not CTOP (10 µ g i.t.), a selective MOR antagonist. Furthermore, intrathecal SNC80 (200 μ g) blocked formalin-induced substance P release otherwise evoked in the ispilateral superficial dorsal horn as measured by NK1 receptor internalization. In conclusion, intrathecal SNC80 alleviated pain hypersensitivity after peripheral inflammation in a fashion paralleling its ability to block peptide transmitter release from small peptidergic afferents, which by its pharmacology appears to represent an effect mediated by a spinal DOR.