Anatomical specificity of acidic saline model of chronic pain and the role of glia in development of chronic hyperalgesia

Research into mechanisms of hyperalgesia is ongoing with the goal of improving the clinical management of chronic pain. Although several animal models of chronic pain are reported in the literature, few address painful muscle conditions such as fibromyalgia. One such model recently developed in Sprague-Dawley rats uses two acidic saline injections in a gastrocnemius muscle five days apart to induce a long-lasting change in bilateral paw withdrawal thresholds. The first objective of this study was to determine if the two injections needed to occur in the same muscle. Paw withdrawal thresholds were measured by applying von Frey filaments to the plantar surface of the hindpaw; the development of hyperalgesia was indicated by a decrease in paw withdrawal threshold. Acidic saline injections were administered in either the right lateral, right medial or left lateral gastrocnemius muscle. All animals received a second injection in the right lateral gastrocnemius muscle. Paw withdrawal thresholds decreased bilaterally in all animal groups demonstrating that hyperalgesia still develops when the site of the first injection is varied. Additionally, animals in which the first muscle injection was substituted with a non-specific treatment (intraperitoneal injection of lipopolysaccharide) also developed bilateral hyperalgesia. These results demonstrate that the mechanism of chronic pain in this model lies outside of the injected muscles and may be mediated primarily by central nervous system structures. Given the role of central glia cells in other pain models it was next assessed whether the development of hyperalgesia could be blocked by pretreatment with minocycline, an inhibitor of glia cell activation. Pretreatment with minocycline prior to the first muscle injection prevented the development of hyperalgesia whereas minocycline was ineffective when administered before the second muscle injection. These data indicate that central processes including glia cell activation play important roles in the development of hyperalgesia in this model of chronic muscle pain and provide a potential target in the development of interventions (physical and pharmacological) aimed at chronic muscle pain.