Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: involvement of peripheral ionotropic glutamate receptors and capsaicin‐sensitive sensory afferents

Abstract

Glutamate receptors have been identified on the peripheral terminals of both primary sensory afferents and sympathetic post-ganglionic neurons, and activation of these receptors produces peripheral sensitization and enhances nociception. Adenosine is an endogenous agent that has a regulatory effect on pain. In brain and spinal cord, adenosine release can be promoted by excitatory amino acids. In the present study, we used in vivo microdialysis to determine whether glutamate also can release adenosine in peripheral tissues. Rats were anesthetized with pentobarbital and microdialysis probes were implanted into the subcutaneous tissue of the plantar aspect of the rat hind paw. Subcutaneous injection of glutamate (50 lL, 0.3-100 lmol) evoked a short-lasting adenosine release immediately following drug injection. Co-administration of either the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocipine maleate (MK-801, 1 nmol) or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline (CNQX, 10 nmol) with glutamate blocked such release, suggesting an involvement of peripheral ionotropic glutamate receptors in this response. Systemic pre-treatment with capsaicin, a neurotoxin selective for unmyelinated sensory afferents, significantly reduced glutamate-evoked peripheral adenosine release, but release was not affected by systemic pre-treatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic nerve efferents. Neither MK-801 nor CNQX blocked 5% formalin-evoked adenosine release, suggesting adenosine release by formalin is not secondary to ionotropic glutamate receptor activation. We conclude that administration of glutamate evokes peripheral adenosine release, and that peripheral ionotropic glutamate receptors on unmyelinated sensory afferents are involved in such release. The released adenosine may provide a negative feedback control on nociception.

Release of algesic substances in human experimental muscle pain

“…The authors suggested that ketamine reduces central hyperexcitability i. e. the site of action of ketamine was thought to be central. However recently, peripheral ionotropic [72] and metabotropic glutamate receptors [73] were found to be involved in nociceptive responses in animal experiments suggesting that a peripheral glutamate release might be involved in peripheral nociceptive mechanisms. In the biceps muscle glutamate levels remained elevated for about 2 h after injection of hypertonic saline.…”

Topical ketamine and morphine for post-tonsillectomy pain

“…There is a growing amount of experimental evidence showing that NMDA receptors are present in the periphery [34,35]. Furthermore, experimental studies indicate that peripherally administered NMDA receptor antagonists are effective in antinociception [36][37][38]. However, the role of the peripheral NMDA receptors in human pain is obscure.…”

Microdialysis of Inflammatory Mediators in the Skin: A Review

“…The release of adenosine in response to injections of formalin or glutamate or to spinal nerve ligation has been studied (33)(34)(35)(36). glutamate administration evoked peripheral adenosine release in the rat hindpaw ( fig.…”

“…Adenosine may play a regulatory role in pain and inflammation in peripheral tissues (33). The release of adenosine in response to injections of formalin or glutamate or to spinal nerve ligation has been studied (33)(34)(35)(36).…”