Topical review The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans Dorit Pud a,b, * , Yelena Granovsky b,c , David Yarnitsky b,c a Faculty of Social Welfare and Health Sciences, University of Haifa, Israel b The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Israel c Department of Neurology, Rambam Medical Center, Haifa, Israel 1. Introduction The exploration of endogenous analgesia (EA) via descending pain-modulatory systems started about three decades ago. The generation of analgesia in the rat by periaquaductal grey (PAG) stimulation was the first evidence for the existence of endogenous analgesic capabilities as a normal function of the central nervous system, exerting both inhibitory and facilatory effects (for review, see [5]). Consequent evidence demonstrated an important final common descending modulatory site in the brainstem, the rostral ventromedial medulla (RVM), which receives signals directly from the PAG, with both bearing opioid receptors. Subsequently, the RVM forwards signals downward to the spinal cord (for review, see [11]). This dorsolateral funiculus descending inhibitory pain pathway, consisting of serotonergic and noradrenergic neurons, is under ‘top-down’ cerebral control, mediating modulation of pain perception by emotional, motivational, and cognitive factors [5,11]. Further important evidence in this regard came in the late 1970s from Le Bars and his colleagues [21,22], who were the first to associate the effectiveness of the commonly known ‘pain-inhib- its-pain’ counter-irritation phenomena with this EA mechanism. They reported that activity in the dorsal horn and trigeminal nuclei is inhibited by the application of noxious electrical stimuli to re- mote body areas in anaesthetized rats [21,22]. This phenomenon was termed ‘diffuse noxious inhibitory controls’ (DNICs). Both elec- trophysiological and anatomical data support the involvement of the subnucleus reticularis dorsalis (SRD) in the caudal medulla in spino-bulbo-spinal loops that are exclusively activated by neurons with a ‘whole-body receptive field’ [23]. Their descending projec- tions pass through the dorsolateral funiculus and terminate in the dorsal horn at all levels of the spinal cord. Thus, DNIC is a ‘bot- tom-up’ activation of the pain-modulatory mechanism, as part of the descending endogenous analgesia (EA) system. In recent years, a DNIC-like effect, also commonly termed HNCS (heterotopic noxious conditioning stimulation), has been identified as an advanced psychophysical measure with high clinical rele- vancy in the characterization of one’s capacity to modulate pain and consequently one’s susceptibility to acquire pain disorders. 2. Experimental methods to evoke the DNIC effect The DNIC-like effect can be studied experimentally in the labo- ratory by measuring the pain intensity for a ‘test’ stimulus before and during or after the application of a noxious ‘conditioning’ stim- ulus. A reduction in the magnitude of the ‘test-pain’ in response to the ‘conditioning stimulus’ is considered as the DNIC effect. Different laboratories take different approaches and employ numerous kinds of experimental settings in healthy subjects as well as in patients in order to evoke the DNIC effect. The diversity starts with the different terminologies describing the same phe- nomenon. As such, some laboratories use the term DNIC, while others use HNCS, EA, or DNIC-like effect. The terms used for the specific stimuli also bear different names. For the sake of consis- tency between laboratories, herein we suggest the use of the fol- lowing terms: ‘DNIC’ for the neurophysiological phenomena; ‘DNIC-like effect’ for the psychophysical paradigm; ‘test-pain’ for the conditioned stimulation; and ‘conditioning stimulus’ for the stimulus generating the effect. Thus far, similar to the case for other psychophysical measures, there are no accepted unified stan- dards for the performance and calculation of DNIC. In addition, studies on DNIC also vary with respect to spatial design (i.e., homo- topic vs. heterotopic and specific body regions examined); tempo- ral characteristics (parallel or sequential stimulation); duration; intensity; ISI and number of stimuli; test-pain parameters (i.e., pain threshold; pain intensity in response to supra-threshold pain- ful stimulation; phasic or tonic stimuli; temporal summation); and neurophysiological evaluations (evoked potentials for laser or elec- trical stimulation and the RIII reflex measured by EMG). The purpose of this topical review is to summarize the com- monly used experimental methods for evoking a DNIC-like effect in young healthy subjects and to show its magnitude. The data are shown in Table 1. The parameters taken into account are the experimental modalities used for the test-pain and the condition- ing stimuli; the examined body regions; the nature of the study (psychophysical or neurophysiological study); and the study sam- ple size. The outcome measure is the maximal DNIC effect (in per- centage) either for the entire sample or according to gender when the relevant data are available. As can be seen from the table, the most commonly used para- digm to evoke a DNIC-like effect is the administration of a noxious conditioning cold stimulus (usually water immersion, the so-called 0304-3959/$36.00 Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2009.02.015 * Corresponding author. Address: Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 31905, Israel. Tel.: +972 4 8288006; fax: +972 4 8288017. E-mail address: doritpud@research.haifa.ac.il (D. Pud). www.elsevier.com/locate/pain PAIN Ò 144 (2009) 16–19