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PNAS u January 10, 2012 u vol. 109 u no. 2 u 347–348 www.pnas.org/cgi/doi/10.1073/iti0212109 Substance P (SP) is a pain neurotransmitter that helps excite and transmit pain signals from neural cells in many organs. Though high levels of SP in muscle tissues and spinal fluid are frequently associated with chronic muscle pain, the role of SP in muscle pain transmission and perception remains unclear. Chia-Ching John Lin et al. (pp. 363–364) used mice that lacked SP signaling to test how SP contributes to muscle pain sensitivity. The researchers found that in contrast to the neurotransmitter’s usual excitatory role, mice without SP signaling showed increased pain sensitivity after intramuscular acid injections compared with mice that had normal SP signaling. Increased sensitivity to muscle pain was noted in mice lacking the gene for SP signaling as well as mice administered compounds designed to bind SP receptors. The finding suggests that SP may inhibit pain sensitization in muscle pain receptors, and may be present in patients with chronic muscle pain as part of an inhibitory feedback loop. The researchers caution that drugs designed to reduce neural reception of SP in fibromyalgia patients—currently in clinical trials—may increase patients’ risk of chronic muscle pain and muscle pain sensitivity. — J.M. Unconventional muscle pain signaling