NMDA-Receptor Antagonists Reduce Skin Sensitivity to the TRPV1-Receptor Agonist Capsaicin

Analysis of the Involvement of NMDA Receptors in Analgesia and Hypothermia Induced by the Activation of TRPV1 Ion Channels

“…Preliminary administration of NMDA receptor antagonists suppressed the capsaicin-induced increase in the threshold of pain sensitivity in the tail flick test reproducing the spinal flexion reflex in mice and shortened the duration of their response (paw licking) to the injection of a capsaicin solution into the metatarsal region in our earlier study [ 12 ]. Intradermal injection of capsaicin into a the paw in rats induced phosphorylation of the NR1 subunit of the NMDA receptors in the neurons of the dorsal horns of the spinal cord and the spinothalamic tract catalyzed by protein kinase A (PKA)- and PKC, which was detected 30 min after capsaicin injection [ 47 , 48 ].…”

“…No significant intergroup differences between animals that received 20 mg/kg BCTC and 40 mg/kg hemantane were detected ( Table 1 ). Single intraperitoneal administration of 20 and 40 mg/kg hemantane shortened the duration of the pain response to subcutaneous injection of a capsaicin solution into the metatarsal region in mice in a dose-dependent manner; therefore, the 40 mg/kg dose of the agent was used in this study [ 12 ].…”

“…A single subcutaneous injection of the high-affinity NMDA receptor antagonist MK-801 at a dose of 20 μg/kg (at this dose, it reduced the duration of the capsaicin-induced pain behavior in mice [ 12 ]) and a larger dose (0.5 mg/kg) had no significant effect on the thermal pain threshold in the tail flick test in mice ( Table 1 ). Interestingly, single administration of MK-801, the high-affinity NMDA receptor antagonist, induced both the pronociceptive [ 30 ] and antinociceptive effects in rats [ 31 ].…”

“…This, however, did not occur: preliminary administration of NMDA receptor antagonists to the animals did not prevent transient capsaicin-induced hypothermia. Therefore, in the mechanism of transient capsaicin-induced hypothermia in mice, we uncovered no functional interplay between TRPV1 ion channels and NMDA receptors that would be similar to that detected in the experiments aiming to assess the pain response in mice in the tail flick test or the duration of the response in mice when the studied TRPV1 agonist was injected into the metatarsal region [ 12 ]. Therefore, our data prove that when administered systemically, capsaicin, a selective TRPV1 ion channel agonist, can penetrate the BBB and act on the neurons in the preoptic area of the hypothalamus, thus affecting thermosensitivity.…”

“…Injection of antagonists of ionotropic NMDA and AMPA or metabotropic mGluR1 glutamate receptors into the plantar surface in rats decreases thermal hyperalgesia induced by capsaicin, a TRPV1 ion channel agonist, and inhibits the elevation of the glutamate level in subcutaneous perfusate observed after the injection of capsaicin into the animals’ metatarsal region [ 11 ]. Noncompetitive antagonists of NMDA receptors (high-affinity (5S,10R)-(+)-5-methyl-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) and low-affinity N-(2-adamantyl)- hexamethyleneimine hydrochloride (hemantane)) reduce the duration of the pain response to the sub cutaneous injection of a capsaicin solution into the metatarsal region of mice when applied dermally, systemically (intraperitoneally for hemantane and subcutaneously for MK-801), and via the subcutaneous intraplantar route [ 12 ].…”