Pain is defined as a sensory and emotional experience associated with actual or potential tissue damage, or described in terms as such (www.iasp-pain.org). Chronic pain is a significant health problem affecting between 20% and 50% of the population; musculoskeletal pain is the most common. Chronic pain interferes with everyday activities including work, recreational activities, and activities of daily living. Acute pain, directly related to a tissue injury, also significantly impacts daily activities. Further, adequate treatment of acute pain is thought to prevent development of chronic pain. Interestingly, only 25% of respondents with pain participate in exercise: 45% of those with chronic pain and 14% of those with acute (for a review, see Sluka, 2009b). One effective treatment common for nearly all types of chronic pain, including those with musculoskeletal pain, is regular exercise (for a review, see Bement, 2009). Regular exercise also produces analgesia in uninjured animals and reduces pain behaviors after inflammatory, noninflammatory, and neuropathic injury (Bement & Sluka, 2005; Blustein, McLaughlin, & Hoffman, 2006; Konarzewski, Sadowski, & Jozwik, 1997; Kuphal, Fibuch, & Taylor, 2007; Mathes & Kanarek, 2006; Shankarappa, Piedras-Renteria, & Stubbs, Jr., 2011; Stagg et al., 2011). In contrast to regular exercise, a single bout of exercise can enhance pain in both humans and animals (Lannersten & Kosek, 2010; Sluka & Rasmussen, 2010; Staud, Robinson, & Price, 2005; Vierck et al., 2001; Yokoyama, Lisi, Moore, & Sluka, 2007). Understanding the mechanisms that underlie these diverse effects of exercise will assist in the development of exercise protocols for patient populations.