Acute peripheral inflammation induces moderate glial activation and spinal IL-1β expression that correlates with pain behavior in the rat

TLDR

Peripheral nerve injury in rats induces spinal glial activation and proinflammatory cytokine upregulation, contributing to neuropathic pain. This study aimed to determine whether acute peripheral inflammation elicits comparable central glial and IL‑1β responses as seen after nerve transection. Male Sprague–Dawley rats received subcutaneous plantar injections of 5 % formalin or 25 mg ml⁻¹ zymosan, were sacrificed at 1 h, 6 h, 1, 3, and 7 days, and spinal L4–L5 sections were examined by immunohistochemistry for glial markers and IL‑1β. Both inflammatory models produced transient pain behaviors and mechanical allodynia that paralleled microglial/astrocytic activation and IL‑1β upregulation, supporting a shared role for glial‑cytokine signaling in hyperalgesia after inflammation or nerve injury.

Abstract

Our laboratory has previously shown that glial activation and increased proinflammatory cytokine expression are observed in the rat spinal cord following peripheral nerve injuries that result in neuropathic pain behaviors. In the present study, we sought to determine whether acute peripheral inflammation induces changes in central glial and cytokine (Interleukin-1β) expression similar to those seen following peripheral spinal nerve transection. Two models of peripheral inflammation were used in this study: formalin (5% solution) or zymosan (25 mg/ml) injected subcutaneously into the plantar portion of the left hind paw of male Holtzman-strain Sprague–Dawley rats. The rats were euthanized at 1 h, 6 h, and 1, 3, 7 days post-injection (n=4 or 5/group/time point). As expected, the animals treated with formalin showed a spontaneous pain response and mechanical allodynia that persisted for approximately 60 min following injection. The animals treated with zymosan exhibited mild spontaneous pain responses during the first hour and mechanical allodynia at 6 h and 1 day following injection. Immunohistochemistry for glial activation and cytokine expression was performed on L4–L5 spinal levels in all rats. Spinal sections from both formalin and zymosan treated animals exhibited microglial and astrocytic activation and increased Interleukin-1β immunoreactivity at 1 and 6 h, respectively. Spinal glial activation and upregulation of Interleukin-1β appear to parallel the development and maintenance of zymosan and formalin-induced mechanical allodynia. These findings support a unifying theory that glial activation and cytokine expression have a similar, if not related, role in producing hyperalgesia following either peripheral inflammation or peripheral nerve injury.