Glycine transporter inhibitors as a potential therapeutic strategy for chronic pain with memory impairment.

Abstract

BACKGROUND:

Impaired excitatory and inhibitory balance in the spinal dorsal horn has a crucial role in the pathophysiology of chronic pain. The authors addressed the therapeutic impact of increasing spinal glycine applied exogenously or via blockade of glycine transporter 1 using its selective inhibitors sarcosine and N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine on neuropathic and inflammatory pain in mice.

METHODS:

Mice with thermal and mechanical hypersensitivity after partial ligation of the sciatic nerve (Seltzer model) or mice with mechanical hypersensitivity after streptozotocin injection received intrathecal injection of glycine, sarcosine, and N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine. These drugs were also intrathecally injected in mice to assess their effects on formalin-evoked nociceptive behaviors. The supraspinal effect of blockade of glycine transporter 1 was studied on tetanus-induced long-term potentiation of the Schaffer-collateral synapses in hippocampal slices prepared from Seltzer model mice.

RESULTS:

Glycine, sarcosine, and N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine ameliorated thermal and mechanical hypersensitivity in Seltzer model mice, and reduced mechanical hypersensitivity in streptozotocin-injected diabetic mice. Moreover, they selectively inhibited the second phase of formalin-evoked licking/biting behavior. In hippocampal slices prepared from Seltzer model mice, long-term potentiation was maintained at a significantly lower level than that in sham-treated mice. Such impairment of long-term potentiation was never observed when it was induced in the presence of N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine.

CONCLUSIONS:

An increase in endogenous glycine via glycine transporter 1 blockade not only results in a net inhibitory influence on pain transmission at the spinal level but also supraspinally relieves decreased synaptic efficacy presumably related to cognitive disturbance often described in patients with chronic pain.

• Authors: Mitsuo Tanabe, Keiko Takasu, Sachiko Yamaguchi, Daisuke Kodama, Hideki Ono
• Journal: Anesthesiology (Anesthesiology) Vol. 108 Issue 5 Pg. 929-37 (May 2008) ISSN: 1528-1175 [Electronic] United States
• PMID: 18431130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Glycine Plasma Membrane Transport Proteins
• N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine
• Glycine
• Sarcosine

Topics

• Acute Disease
• Analgesics (therapeutic use)
• Animals
• Diabetes Mellitus, Experimental (physiopathology)
• Diabetic Neuropathies (drug therapy)
• Glycine (therapeutic use)
• Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors)
• Hypersensitivity (drug therapy)
• Long-Term Potentiation (drug effects, physiology)
• Male
• Mice
• Mice, Inbred Strains
• Pain (drug therapy)
• Sarcosine (analogs & derivatives, therapeutic use)