Hyperalgesia Mediated By Spinal Prostaglandin E2 And Signalling Through The P38 Pathway In Diabetic Rats

Abstract

Diabetic rats exhibit hyperalgesia following paw formalin injection, despite reduced spinal release of the excitatory neurotransmitters substance P and glutamate. In normal rats, spinal sensitization to sensory input involves local release of prostaglandin E2 (PGE2). We used microdialysis to measure spinal PGE2 release following paw formalin injection in conscious control and STZ‐diabetic rats. In control rats, there was an increase in spinal PGE2 levels to 260 ± 14% of basal (p < 0.01) in the first 5 minutes after paw formalin injection and thereafter levels were not different from basal. Diabetic rats showed a similar increase (254 ± 25%) but also exhibited a second period of release (266 ± 20%; p < 0.01 vs. basal) 15‐20 minutes after the stimulus. Systemic delivery of the NSAID indomethacin (10 mg/kg IP) or intrathecal delivery of an EP1 receptor antagonist (30 μg) prior to paw formalin injection both significantly reduced the number of paw flinches in diabetic rats 10‐40 minutes after injection (17 ± 9 and 20 ± 8, respectively) compared to vehicle treated diabetics (42 ± 8). Formalin‐evoked flinching was also significantly reduced by spinal delivery of the p38 stress‐activated protein kinase inhibitor SB203580 (1–30 μg IT) in both control and diabetic rats, with higher concentrations required for efficacy in diabetic rats. Hyperalgesia following paw formalin injection in diabetic rats is accompanied by increased spinal PGE2 release and activation of the EP1 receptor while signaling through the p38 pathway also participates in maintaining formalin‐evoked flinching.