Figure 1.

(A) Illustration of hyperalgesic priming. A single priming stimulus produces a short-lived hyperalgesic response that resolves (green). A second inducing stimulus, given within a critical window, will then produce a longer-lasting and more robust hyperalgesia (orange). For comparison the initial priming response is overlayed on the enhanced response. Copyright by Dr. Kathleen Sluka. (B) Intraomuscular injection of pH 4.0 produces a short duration decrease in withdrawal threshold to mechanical stimulation of the paw. A second injection 5 days later produces a greater and longer lasting decrease in withdrawal threshold. Reproduced with permission from(5). (C) Injection of NGF into human masseter (MA) muscle caused a decrease in masseter muscle pressure pain thresholds (PPT) at day 1 and day 7 following injection. This effect was localized to the masseter muscle since no decrease in PPT at the masseter muscle was seen following injection of NGF into the temporalis (TA) muscle. Muscle contraction produces pain over the tibialis anterior muscle after NGF injection that results in a greater area of pain after several days. Reproduced with permission from(33, 34). (D) Model of peripheral mediators implicated in the development of pain. Fatigue metabolites (H+, ATP) and nerve growth factor (NGF) secreted from muscles activate nociceptors by binding to their receptors. Fatigue metabolites also activate macrophages to increase the production of inflammatory cytokines which work to activate nociceptors. Copyright by Dr. Kathleen Sluka.