A novel animal model of graded neuropathic pain: utility to investigate mechanisms of population heterogeneity

Abstract

The mechanisms underlying neuropathic pain are not well understood, resulting in unsatisfactory treatment outcomes for many patients. Animal models underpin much of the current understanding of pain mechanisms due to their perceived ability to mimic pain hypersensitivities; however, are limited by their binomial approach (pain vs. control), which does not reflect the clinical heterogeneity in nociceptive hypersensitivity. We modified the chronic constriction injury model by varying the number of sciatic nerve chromic gut sutures. Each Sprague Dawley rat received 4 pieces of chromic gut to control for the inflammatory challenge posed by the gut. Treatment groups were neuronal sutures (N), subcutaneous sutures (S) N0S0, N0S4, N1S3, N2S2 and N4S0. At postoperative (PO) day 29, there was a 'dose-response' relationship between the number of perineural sutures and von Frey threshold (N0S4<N1S3<N2S2<N4S0, P<0.05). This graded model was applied to investigate lumbar dorsal spinal cord glial activation marker expression. Microglial CD11b expression was positively correlated with graded allodynia in the ipsilateral dorsal horn (P<0.05, r(2)>0.9) and associated in the dorsolateral funiculus (DLF; P=0.10, r(2)>0.8) at PO day 14. Astrocyte GFAP expression was positively associated with graded allodynia in the ipsilateral dorsal horn (P=0.18, r(2)>0.6) and ipsilateral DLF (P<0.05, r(2)>0.9). DLF glial activation may represent a contributor to contralateral pain. Our novel graded model has a dynamic range, allowing sensitive detection of interactions and subtle influences on neuropathic pain processing.