an

ences in cortical and subcortical activity. In general, widespreaddeactivations were observed in a number of classical pain-related

pattern of neurobiological activity in areas involved in pain per-ception and modulation. More importantly, the study adds tothe discussion about the methods and implications of different

regions reported in recent imaging studies (ie, PAG, Anterior Cin-gulate Cortex [22,24]). Thus, depending on the presentation of the

r in termxperimen

antagonism [18], a nding that contrasts with OA, which appearsto be resistant to these manipulations [14,19,18]. Recently, similardifferences were observed with tapentadol [20], a dual l-opioidreceptor agonist and norepinephrine reuptake inhibitor. Severalweeks of treatment restored the inhibitory capacity assessed byCPM in patients with diabetic polyneuropathy but not affect OA,suggesting differential neuromodulatory tone underlying eachparadigm.qDOI of original article: http://dx.doi.org/10.1016/j.pain.2014.07.008

PAIN155 (2014) 244dependent on the spatial (CPM) and temporal (OA) presentationof nociceptive information, which in turn results in a differential

pharmacological manipulations, CPM appears to be sensitive toopioids [9,21,26] and the N-methyl-D-aspartate (NMDA) receptorareas during CPM, which was contrasted by activation in a num-ber of areas including the brain stem region associated with theperiaqueductal gray (PAG) during the OA paradigm. Based onthe current study, differences in the modulation of pain are

engaged.In addition, CPM and OA paradigms can diffe

underlying neurotransmitter system. Based on ehttp://dx.doi.org/10.1016/j.pain.2014.08.0170304-3959/ 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.s of thets withtesting and conditioning stimuli, different mechanisms may beCommentary

Conditioned pain modulation and offsetinhibit pain

The ability of the body to modulate sensory information hasbeen a focus of a number of studies over the past several years.Experimentally, pain modulation can be assessed by a number ofmethods including conditioned pain modulation (CPM) and offsetanalgesia (OA) as highlighted in the current study by Nahman-Averbuch et al. [15]. CPM is frequently demonstrated through thereductions of a primary painful stimulus (ie, focal heat) by a secondremote conditioning stimulus (ie, cold water immersion[6,9,17,22,23]). In contrast, OA is demonstrated by using a pro-longed thermal pulse in which a slight reduction in the thermodetemperature (ie, 1C) is associated with a transient (10 s) reduc-tion in pain intensity [7,15,16,18,29,30]. Although only a smallnumber of studies have evaluated CPM and OA in the same cohort[8,17,18,20], the combined use of these inhibitory models may pro-vide a glimpse into different characteristics underlying an individ-uals inhibitory phenotype, which could have implications forfuture experimental and clinical research.

The study by Nahman-Averbuch et al. [15] was designed toinvestigate differences between the psychophysical and neuralcorrelates of CPM and OA. Using the same thermal stimulationparadigm (ie, 30 s prolonged pulse at 49C applied to the leg),the studies demonstrated reductions in the subjective ratings ofheat pain during both concurrent immersion of the contralateralfoot into moderately painful cold water bath (CPM induction)and following a 1C temperature drop (OA induction)observa-tions that are in agreement with those of previous studies[6,7,9,10,15,16,23,30]. However, the magnitude of inhibitionobserved in the 2 models did not correlate suggesting differentmechanisms underlying inhibition. Conrming the psychophysi-cal data, fMRI assessment of each paradigm demonstrated differ-algesia: Different avenues to

inhibitory mechanisms (CPM vs OA) and within different inhibi-tory paradigms (variations of CPM).

What does the current study tell us about pain modulation?

The ndings of the study suggest that experimental manipula-tions, which result in comparable magnitudes of subjective inhibi-tion, may be a consequence of different neurobiologicalmechanisms. This concept is neither surprising nor unexpected,but the current study demonstrates the complexity of nervoussystem in regulating sensory information through multipleneurological structures and neurotransmitters depending on thepresentation of the stimulus.

Interestingly, the authors comment that inhibition during CPMappears to be due to spinal inhibition rather than descendingmodulation. CPM reects the psychophysical representation [28]of the previously described phenomenon termed diffuse noxiousinhibitory control, referring to observations by Le Bars and col-leagues in which activity within the lower aspect of the brainstem suppresses activity within the spinal cord [11,12], whichcan be indirectly modulated by activity within the PAG [2] andthe rostral ventromedial medulla [1]. In contrast, OA is associatedwith increased activity within the PAG and rostral ventromedialmedulla [4,29], although a peripheral component may also exist[16]. Thus, CPM represents a subjective response to a range ofpossible mechanisms, which may include the originally proposedspino-bulbo-spinal loop described by Le Bars and colleagues, aspinal-mediated mechanism proposed by Nahman-Averbuchet al. [15], as well as brain stem, and/or higher-order cortical

www.e l sev ie r . com/ loca te /pa in

42445

What are the clinical implications of multiple pain modulatorymechanisms?

The current study also has clinical implications for the evalua-tion of pain modulation models. Although a reduced capacity toinhibit pain during CPM is commonly observed in clinical pain

including CPM (ie, different conditioning stimuli, temporal and

[8] Honigman L, Yarnitsky D, Sprecher E, Weissman-Fogel I. Psychophysicaltesting of spatial and temporal dimensions of endogenous analgesia:conditioned pain modulation and offset analgesia. Exp Brain Res 2013;228:493501.

[9] King CD, Goodin B, Kindler LL, Caudle RM, Edwards RR, Gravenstein N, Riley3rd JL, Fillingim RB. Reduction of conditioned pain modulation in humans bynaltrexone: an exploratory study of the effects of pain catastrophizing. J Behav

Commentary / PAIN155 (2014) 24442445 2445spatial presentation of stimuli) alter these neurological proles inaddition to how these mechanisms differ in individuals withchronic pain. I anticipate that the current study will encourageadditional investigation into the neurobiological mechanismsunderlying inhibition.

Conict of interest

The author is aware of no conicts of interest regarding thiscommentary.

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Christopher D. KingUniversity of Florida Pain Research and Intervention Center of Excellence

(PRICE), Gainesville, FL 32610, USAE-mail address: cking@dental.u.edu

Conditioned pain modulation and offset analgesia: Different avenues to inhibit painWhat does the current study tell us about pain modulation?What are the clinical implications of multiple pain modulatory mechanisms?Conflict of interestReferences