TY - JOUR
T1 - Menthol facilitates excitatory and inhibitory synaptic transmission in rat medullary dorsal horn neurons
AU - Choi, In Sun
AU - Cho, Jin Hwa
AU - Nakamura, Michiko
AU - Jang, Il Sung
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes. The menthol-induced increase in sEPSC frequency could be completely blocked by AMTB, a TRPM8 antagonist, but was not blocked by HC-030031, a transient receptor potential ankyrin 1 (TRPA1) antagonist. Menthol still increased sEPSC frequency in the presence of Cd2+, a general voltage-gated Ca2+ channel blocker, suggesting that voltage-gated Ca2+ channels are not involved in the menthol-induced increase in sEPSC frequency. However, menthol failed to increase sEPSC frequency in the absence of extracellular Ca2+, suggesting that TRPM8 on primary afferent terminals is Ca2+ permeable. On the other hand, menthol also increased sIPSC frequency, without affecting current amplitudes. The menthol-induced increase in sIPSC frequency could be completely blocked by either AMTB or CNQX, an AMPA/KA receptor antagonist, suggesting that the indirect increase in excitability of inhibitory interneurons may lead to the facilitation of spontaneous GABA and/or glycine release. The present results suggested that menthol exerts analgesic effects, via the enhancement of inhibitory synaptic transmission, through central feed-forward neural circuits within the medullary dorsal horn region.
AB - Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes. The menthol-induced increase in sEPSC frequency could be completely blocked by AMTB, a TRPM8 antagonist, but was not blocked by HC-030031, a transient receptor potential ankyrin 1 (TRPA1) antagonist. Menthol still increased sEPSC frequency in the presence of Cd2+, a general voltage-gated Ca2+ channel blocker, suggesting that voltage-gated Ca2+ channels are not involved in the menthol-induced increase in sEPSC frequency. However, menthol failed to increase sEPSC frequency in the absence of extracellular Ca2+, suggesting that TRPM8 on primary afferent terminals is Ca2+ permeable. On the other hand, menthol also increased sIPSC frequency, without affecting current amplitudes. The menthol-induced increase in sIPSC frequency could be completely blocked by either AMTB or CNQX, an AMPA/KA receptor antagonist, suggesting that the indirect increase in excitability of inhibitory interneurons may lead to the facilitation of spontaneous GABA and/or glycine release. The present results suggested that menthol exerts analgesic effects, via the enhancement of inhibitory synaptic transmission, through central feed-forward neural circuits within the medullary dorsal horn region.
KW - Medullary dorsal horn
KW - Menthol
KW - Pain
KW - Patch clamp
KW - sEPSCs
KW - sIPSCs
KW - TRPM8
UR - http://www.scopus.com/inward/record.url?scp=85092626325&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2020.147149
DO - 10.1016/j.brainres.2020.147149
M3 - Article
C2 - 33035497
AN - SCOPUS:85092626325
SN - 0006-8993
VL - 1750
JO - Brain Research
JF - Brain Research
M1 - 147149
ER -