kt-5720 and Diabetes-Mellitus

We examined the tail-flick response to various heat intensities in diabetic and non-diabetic mice. Heat intensities were set to one of five values by adjusting the source voltage of a 50-W projection bulb to 25, 35, 50, 65 and 80 V. These heat intensities produced surface skin heating rates of 0.1, 0.4, 0.9, 3.0 and 7.3 degrees C/s, respectively. Tail-flick latencies at source voltages of 35 and 50 V in diabetic mice were significantly shorter than those in non-diabetic mice. However, there were no significant differences in tail-flick latencies at 25, 65 and 80 V. In non-diabetic mice, tail-flick latencies were not affected by intrathecal (i.t.) pretreatment with capsaicin 24 h before testing. Tail-flick latencies at 35 and 50 V in diabetic mice were increased by pretreatment with capsaicin. Moreover, although tail-flick latencies in non-diabetic mice were not affected by i.t. pretreatment with calphostin C, a selective protein kinase C inhibitor, those at 35 and 50 V in diabetic mice were increased. However, i.t. pretreatment with (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2, 3, 9, 10-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo [a, g]cycloocta[cde]-trinden-1-one (KT5720), a selective protein kinase A inhibitor, did not affect tail-flick latencies in either diabetic or non-diabetic mice. In non-diabetic mice, i.t. pretreatment with phorbol 12,13-dibutyrate (PDB), a protein kinase C activator, decreased tail-flick latencies at 35 and 50 V. Tail-flick latencies in diabetic mice were not affected by i.t. pretreatment with PDB 60 min before testing. Furthermore, the attenuation of tail-flick latencies induced by i.t. pretreatment with PDB in non-diabetic mice was reversed by i.t. pretreatment with capsaicin 24 h before testing. These results indicate that diabetic mice exhibit thermal allodynia and hyperalgesia. Furthermore, this thermal allodynia and hyperalgesia in diabetic mice may be due to the enhanced release of substance P followed by activation of protein kinase C in the spinal cord.

Topics: Analysis of Variance; Animals; Capsaicin; Carbazoles; Carcinogens; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Enzyme Inhibitors; Hot Temperature; Hyperalgesia; Indoles; Male; Mice; Mice, Inbred ICR; Naphthalenes; Pain; Pain Measurement; Phorbol 12,13-Dibutyrate; Protein Kinase C; Pyrroles; Spinal Cord