*For correspondence: blivisd@ ninds.nih.gov † These authors contributed equally to this work Competing interests: The authors declare that no competing interests exist. Funding: See page 20 Received: 23 November 2016 Accepted: 22 May 2017 Published: 24 May 2017 Reviewing editor: Peggy Mason, University of Chicago, United States This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Identification of a novel spinal nociceptive-motor gate control for Ad pain stimuli in rats Dvir Blivis 1 * † , Gal Haspel 1,2† , Philip Z Mannes 3 , Michael J O’Donovan 1 , Michael J Iadarola 4 1 Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; 2 Federated Department of Biological Sciences, New Jersey Institute of Technology, and Rutgers, Newark, United States; 3 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, United States; 4 Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, United States Abstract Physiological responses to nociceptive stimuli are initiated within tens of milliseconds, but the corresponding sub-second behavioral responses have not been adequately explored in awake, unrestrained animals. A detailed understanding of these responses is crucial for progress in pain neurobiology. Here, high-speed videography during nociceptive Ad fiber stimulation demonstrated engagement of a multi-segmental motor program coincident with, or even preceding, withdrawal of the stimulated paw. The motor program included early head orientation and adjustments of the torso and un-stimulated paws. Moreover, we observed a remarkably potent gating mechanism when the animal was standing on its hindlimbs and which was partially dependent on the endogenous opioid system. These data reveal a profound, immediate and precise integration of nociceptive inputs with ongoing motor activities leading to the initiation of complex, yet behaviorally appropriate, response patterns and the mobilization of a new type of analgesic mechanism within this early temporal nociceptive window. DOI: 10.7554/eLife.23584.001 Introduction Assessment of responses to nociceptive stimuli in either animals or humans is a cornerstone of pain research upon which many inferences from experimental, pharmacological and clinical investigations are based (Kruger and Light, 2010; Szallasi, 2010). However, our appreciation of the full range of behavioral and physiological parameters that comprise a ‘nociceptive response’ remains incomplete, as does our appreciation of the integration of this information at the spinal level. This in turn affects the ability to interpret the results of interventions and manipulations of nociceptive circuits and par- ticipating molecular circuits. Time and magnitude are two, of many, domains in which human and animal behavioral responses are quantified following application of noxious stimuli and from which endpoints can be derived. However, when considering acute and chronic pain, responses in the tem- poral and magnitude domains occupy an extraordinarily broad range. Among the earliest, are action potentials from primary afferent nociceptive fibers and reflex withdrawal responses (Creed and Sherrington, 1926; Jensen et al., 2015; Levinsson et al., 2002; Lundberg, 1979; Morgan, 1998) followed by limb withdrawal reactions (Burke et al., 1971; Lundberg, 1979; Morgan, 1998). Over the longer-term, more integrated behavioral endpoints are measurable such as limb guarding, Blivis et al. eLife 2017;6:e23584. DOI: 10.7554/eLife.23584 1 of 24 RESEARCH ARTICLE