Fig. 2.
Intrathecal administration of the acetaminophen-derived metabolite, N-acylphenolamine (AM404), induces analgesia in behavioral experiments, and direct application of AM404 to the spinal cord increases the frequency of miniature excitatory postsynaptic currents (mEPSCs) sensitive to presynaptic transient receptor potential vanilloid 1, but not cannabinoid 1, receptors on substantia gelatinosa neurons. (A) Mechanical thresholds for paw withdrawal during von Frey stimulation were not affected by AM404, although withdrawal latencies during the radiant heat test were significantly and concentration-dependently prolonged by AM404. AM404 was injected intrathecally at 0.1, 0.3, and 1 nmol (n = 6; *P < 0.05, **P < 0.01, two-way repeated-measures ANOVA with time and drug dose as variables followed by Bonferroni post hoc comparisons). (B) Using in vitro whole cell patch-clamp recordings from substantia gelatinosa neurons of the spinal cord dorsal horn, direct administration of AM404 (30 μM, 2 min) to the spinal cord did not change the mean mEPSC amplitude and had no effect on the cumulative distribution of mEPSC amplitudes. In contrast, AM404 significantly increased the mean mEPSC frequency and induced a significant leftward shift in the cumulative interevent interval distribution of the mEPSCs (n = 7; *P < 0.05, **P < 0.01, paired Student’s t test). The top horizontal scale bar represents 30 s, and the top vertical bar represents 10 pA. The bottom horizontal scale bar represents 500 ms, and the bottom vertical bar represents 10 pA. (C) In the presence of the transient receptor potential vanilloid 1 receptor antagonist capsazepine (CPZ; 10 μM), the AM404-induced increase in mEPSC frequency was not observed (n = 7). The horizontal scale bar represents 30 s, and the vertical bar represents 10 pA. (D) In the presence of the cannabinoid 1 receptor antagonist AM251 (3 μM), a significant AM404-induced increase in mEPSC frequency was observed (n = 7; *P < 0.05, paired Student’s t test). The horizontal scale bar represents 30 s, and the vertical bar represents 10 pA. The data are given as means ± SDs. TTX = tetrodotoxin.

Intrathecal administration of the acetaminophen-derived metabolite, N-acylphenolamine (AM404), induces analgesia in behavioral experiments, and direct application of AM404 to the spinal cord increases the frequency of miniature excitatory postsynaptic currents (mEPSCs) sensitive to presynaptic transient receptor potential vanilloid 1, but not cannabinoid 1, receptors on substantia gelatinosa neurons. (A) Mechanical thresholds for paw withdrawal during von Frey stimulation were not affected by AM404, although withdrawal latencies during the radiant heat test were significantly and concentration-dependently prolonged by AM404. AM404 was injected intrathecally at 0.1, 0.3, and 1 nmol (n = 6; *P < 0.05, **P < 0.01, two-way repeated-measures ANOVA with time and drug dose as variables followed by Bonferroni post hoc comparisons). (B) Using in vitro whole cell patch-clamp recordings from substantia gelatinosa neurons of the spinal cord dorsal horn, direct administration of AM404 (30 μM, 2 min) to the spinal cord did not change the mean mEPSC amplitude and had no effect on the cumulative distribution of mEPSC amplitudes. In contrast, AM404 significantly increased the mean mEPSC frequency and induced a significant leftward shift in the cumulative interevent interval distribution of the mEPSCs (n = 7; *P < 0.05, **P < 0.01, paired Student’s t test). The top horizontal scale bar represents 30 s, and the top vertical bar represents 10 pA. The bottom horizontal scale bar represents 500 ms, and the bottom vertical bar represents 10 pA. (C) In the presence of the transient receptor potential vanilloid 1 receptor antagonist capsazepine (CPZ; 10 μM), the AM404-induced increase in mEPSC frequency was not observed (n = 7). The horizontal scale bar represents 30 s, and the vertical bar represents 10 pA. (D) In the presence of the cannabinoid 1 receptor antagonist AM251 (3 μM), a significant AM404-induced increase in mEPSC frequency was observed (n = 7; *P < 0.05, paired Student’s t test). The horizontal scale bar represents 30 s, and the vertical bar represents 10 pA. The data are given as means ± SDs. TTX = tetrodotoxin.

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