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Endogenous pain inhibition is less efficient in chronic pain patients. Diffuse noxious inhibitory control (DNIC), a form of endogenous pain inhibition, is compromised in women and older people, making them more vulnerable to chronic pain. However, the underlying mechanisms remain unclear. Here, we used a capsaicin-induced DNIC test and resting-state functional MRI to investigate the impact of aging and sex on endogenous pain inhibition and associated brain circuitries in healthy rats. We found that DNIC was less efficient in young females compared with young males. Diffuse noxious inhibitory control response was lost in old rats of both sexes, but the brain networks engaged during DNIC differed in a sex-dependent manner. Young males had the most efficient analgesia with the strongest connectivity between anterior cingulate cortex (ACC) and periaqueductal gray (PAG). The reduced efficiency of DNIC in young females seemed to be driven by widespread brain connectivity. Old males showed increased connectivity between PAG, raphe nuclei, pontine reticular nucleus, and hippocampus, which may not be dependent on connections to ACC, whereas old females showed increased connectivity between ACC, PAG, and more limbic regions. These findings suggest that distinct brain circuitries including the limbic system may contribute to higher susceptibility to pain modulatory deficits in the elderly population, and sex may be a risk factor for developing age-related chronic pain.

Diffuse noxious inhibitory controls (DNICs) is a pain-inhibits-pain phenomenon demonstrated in humans and animals. Diffuse noxious inhibitory control is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. Little is known as to why DNIC is dysfunctional in neuropathic pain. Here, we evaluated DNIC in the rat L5/L6 spinal nerve ligation (SNL) model of chronic pain using both behavioral and electrophysiological outcomes. For behavior, nociceptive thresholds were determined using response to noxious paw pressure on both hind paws as the test stimulus before, and after, injection of a conditioning stimulus of capsaicin into the left forepaw. Functionally, the spike firing of spinal wide-dynamic-range neuronal activity was evaluated before and during noxious ear pinch, while stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (ie, injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (ie, uninjured) paw. Systemic application of nor-binaltorphimine, a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-binaltorphimine into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the right central amygdala to promote diminished DNIC after neuropathy.

The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.

In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNICs). One hundred and seventeen client-owned dogs were recruited to the study. Hind limb nociceptive withdrawal reflex thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving nonsteroidal anti-inflammatory drugs (OANSAIDs), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. Nociceptive withdrawal reflex thresholds were higher in OA compared with control dogs (P = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (P < 0.001) and control (P < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre-mediated responses in both OA (P < 0.001) and OANSAID (P = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (P < 0.001); control animals demonstrated greater inhibition compared with OA (P = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA and demonstrate that canine OA is associated with reduced DNIC.

The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.

Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

Electrical stimulation of low-threshold Aβ-fibers (Aβ-ES) is used clinically to treat neuropathic pain conditions that are refractory to pharmacotherapy. However, it is unclear how Aβ-ES modulates synaptic responses to high-threshold afferent inputs (C-, Aδ-fibers) in superficial dorsal horn. Substantia gelatinosa (SG) (lamina II) neurons are important for relaying and modulating converging spinal nociceptive inputs. We recorded C-fiber-evoked excitatory postsynaptic currents (eEPSCs) in spinal cord slices in response to paired-pulse test stimulation (500 μA, 0.1 millisecond, 400 milliseconds apart). We showed that 50-Hz and 1000-Hz, but not 4-Hz, Aβ-ES (10 μA, 0.1 millisecond, 5 minutes) induced prolonged inhibition of C-fiber eEPSCs in SG neurons in naive mice. Furthermore, 50-Hz Aβ-ES inhibited both monosynaptic and polysynaptic forms of C-fiber eEPSC in naive mice and mice that had undergone spinal nerve ligation (SNL). The paired-pulse ratio (amplitude second eEPSC/first eEPSC) increased only in naive mice after 50-Hz Aβ-ES, suggesting that Aβ-ES may inhibit SG neurons by different mechanisms under naive and nerve-injured conditions. Finally, 50-Hz Aβ-ES inhibited both glutamatergic excitatory and GABAergic inhibitory interneurons, which were identified by fluorescence in vGlut2-Td and glutamic acid decarboxylase-green fluorescent protein transgenic mice after SNL. These findings show that activities in Aβ-fibers lead to frequency-dependent depression of synaptic transmission in SG neurons in response to peripheral noxious inputs. However, 50-Hz Aβ-ES failed to induce cell-type-selective inhibition in SG neurons. The physiologic implication of this novel form of synaptic depression for pain modulation by Aβ-ES warrants further investigation.

Recent human neuroimaging studies have investigated the neural correlates of either noxious stimulus intensity or reported pain. Although useful, analyzing brain relationships with stimulus intensity and behavior separately does not address how sensation and pain are linked in the central nervous system. In this study, we used multi-level mediation analysis to identify brain mediators of pain—regions in which trial-by-trial responses to heat explained variability in the relationship between noxious stimulus intensity (across 4 levels) and pain. This approach has the potential to identify multiple circuits with complementary roles in pain genesis. Brain mediators of noxious heat effects on pain included targets of ascending nociceptive pathways (anterior cingulate, insula, SII, and medial thalamus) and also prefrontal and subcortical regions not associated with nociceptive pathways per se. Cluster analysis revealed that mediators were grouped into several distinct functional networks, including the following: somatosensory, paralimbic, and striatal-cerebellar networks that increased with stimulus intensity; and 2 networks co-localized with ‘‘default mode’’ regions in which stimulus intensity-related decreases mediated increased pain. We also identified ‘‘thermosensory’’ regions that responded to increasing noxious heat but did not predict pain reports. Finally, several regions did not respond to noxious input, but their activity predicted pain; these included ventromedial prefrontal cortex, dorsolateral prefrontal cortex, cerebellar regions, and supplementary motor cortices. These regions likely underlie both nociceptive and non-nociceptive processes that contribute to pain, such as attention and decision-making processes. Overall, these results elucidate how multiple distinct brain systems jointly contribute to the central generation of pain.

The analgesic effect of heterotopic noxious counter-stimulation (HNCS; "pain inhibits pain") has been shown to decrease in older persons, while some neuropsychological studies have suggested a reduction in cognitive inhibition with normal aging. Taken together, these findings may reflect a generalized reduction in inhibitory processes. The present study assessed whether the decline in the efficacy of pain inhibition processes is associated with decreased cognitive inhibition in older persons. Healthy young (18-46 years old; n=21) and older (56-75 years old; n=23) adult volunteers participated in one experimental session to assess the effect of HNCS (cold pain applied on the left forearm) on shock pain and RIII reflex induced by transcutaneous electrical stimulation of the right sural nerve. In the same session, participants also performed a modified Stroop task, including a target condition requiring the frequent switching between inhibition and no inhibition of the meaning of color words. The analgesic effect induced by HCNS was significantly smaller in older participants for both shock-pain ratings (P

Heterotopic noxious counterstimulation (HNCS) by the application of a sustained noxious stimulus has been shown to inhibit nociceptive processes and decrease pain induced by a competing noxious stimulus. However, it is still not clear how attentional processes contribute to these effects. The main objective of this study was to compare the analgesic effects of HNCS in 2 sessions during which top-down attention was manipulated. Acute shock pain and the nociceptive flexion reflex were evoked by transcutaneous electrical stimulations of the right sural nerve in 4 blocks (15 stimuli/block): baseline, heterotopic innocuous counterstimulation (HICS), HNCS, and recovery. Counterstimulation was applied on the left upper limb with a thermode (HICS) or a cold pack (HNCS). Attention was manipulated between sessions by instructing participants to focus their attention on shock pain or counterstimulation. Shock pain ratings decreased significantly during counterstimulation (P < .001) with stronger effects of HNCS vs HICS in both sessions (P < .01). Furthermore, shock pain inhibition during HNCS relative to baseline was stronger with attention focusing on counterstimulation compared to attention focusing on shocks (P = .015). However, the relative decrease in pain ratings during HNCS vs HICS was not significantly affected by the direction of attention (P = .7). As for spinal nociceptive processes, nociceptive flexion reflex amplitude was significantly decreased during counterstimulation (P < .001) with larger reductions during HNCS compared to HICS (P = .03). However, these effects were not altered by attention (P = .35). Together, these results demonstrate that top-down attention and HNCS produce additive analgesic effects. However, attentional modulation of HNCS analgesia seems to depend on supraspinal processes.

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models.

Episodic migraine (EM) may evolve into the more disabling chronic migraine (CM, monthly migraine days ⩾ 8 and headache days ⩾ 15) with unknown mechanism. Aiming to elucidate the pathophysiology of CM and its relationship with EM, this study characterized the visual cortical responses in CM and EM. Neuromagnetic visual-evoked responses to left-hemifield checkerboard reversals were obtained in patients with EM (interictal or ictal states), CM (interictal) and age-matched controls. For each subject, the 1500 evoked responses were sequentially divided into 30 blocks and percentage changes of P100m amplitude in blocks 2, 9, 16, 23, and 30 compared to the first block were computed to assess habituation. At the end of visual stimulation (block 30), P100m amplitude was decreased (habituated) in the controls (n = 32) (35.2 ± 2.6 nAm vs. 41.9 ± 2.7, p = 0.005) but increased (potentiated) in the interictal state of EM (n = 29) (39.7 ± 3.8 vs. 33.5 ± 3.0, p = 0.007). In CM (n = 25), P100m was habituated (46.5 ± 2.9 vs. 51.6 ± 3.7, p = 0.013) but higher at the initial block than in those of the interictal state of EM (p = 0.001). These CM features also characterized the P100m in the ictal state of EM (n = 9). There was no difference of P100m between CM and ictal state of EM. In conclusion, patients with CM demonstrate a persistent ictal-like excitability pattern of the visual cortex between migraine attacks which may implicate central inhibitory dysfunction.

Transcutaneous electrical nerve stimulation (TENS) is a noninvasive modality used to control pain. Animal models show that repeated TENS application produces analgesic tolerance and cross-tolerance at spinal opioid receptors. The aim of the present investigation was to examine whether repeated application of TENS produces analgesic tolerance in humans. One hundred healthy subjects were randomly assigned to 1 of 4 groups: control, placebo, low-frequency (4Hz) or high-frequency (100Hz) TENS. TENS was applied daily for 5days to the nondominant upper limb; pressure-pain threshold (PPT) measurements were recorded before and after TENS. Temporal summation to mechanical stimulation was recorded on days 1 and 5, before and after TENS. Diffuse noxious inhibitory control (DNIC) was tested on day 5 using the cold pressor test and PPT measurements. There was an initial increase in PPTs in both low- and high-frequency TENS groups when compared with placebo or control groups. However, by day 5 this TENS-induced increase in PPT did not occur, and there was no difference between active TENS and placebo or control groups. High-frequency TENS decreased temporal summation on day 1 when compared with day 5. DNIC increased the PPT similarly in all groups. These data suggest that repeated daily application of TENS results in a decrease in its hypoalgesic effect by the fifth day and that the tolerance-like effect to repeated TENS results from tolerance at centrally located opioid receptors. The lack of change in DNIC response suggests that TENS and DNIC utilize separate pathways to produce analgesia. Repeated high-frequency and low-frequency transcutaneous electrical nerve stimulation produce analgesic tolerance in humans by the fourth and fifth day of treatment, respectively.

Over the last decade, extensive research has demonstrated sex differences in pain perception and modulation. Several factors have been proposed to account for the differences observed between men and women, including pain modulation through diffuse noxious inhibitory controls (DNIC). Studies investigating sex differences in DNIC have shown mixed results, with some reporting decreased DNIC effect in women compared with men, while others found no difference in DNIC between the sexes. Additional studies have investigated DNIC in both sexes without focusing on sex differences. This systematic review aimed to answer the following question: "In humans of reproductive age without chronic pain, are women more likely than men to have decreased Diffuse Noxious Inhibitory Controls?" Relevant studies were identified by computerized searches of Pubmed/Medline, Embase, Biosis, Web of Science, PsycInfo and Cochrane (from January 1980 through February 2009). The search was limited to human studies with no language restriction. The initial search identified 718 titles and abstracts. Seventeen studies were included in the final stage and data regarding age and gender of participants, methodology and outcome measurements were extracted and analyzed. The majority of studies using pain report as the outcome found significantly more efficient DNIC in males than females (mean female/male ratio=0.54). Studies evaluating pain thresholds and nociceptive flexion reflex indicated the opposite when simply averaged across studies; however, weighted analyses of threshold found more efficient DNIC in males. Gender differences in DNIC effect depend on both the experimental methodology and the modes of measurement of the effect.

'Diffuse noxious inhibitory controls' (DNIC), a form of supraspinal descending endogenous analgesia, requires a noxious conditioning stimulus for pain attenuation. This may be partly dependent on a distraction effect. The term "conditioned pain modulation" (CPM) has recently been introduced to describe the psychophysical paradigm to test DNIC. The present study aimed to determine whether distraction and tonic heat stimulation inhibit pain through the same or different mechanisms by looking at whether there is a similar or even an additive effect on pain attenuation. Test pain was brief heat stimulation applied to the left volar of 34 healthy volunteers. For conditioning, the right hand was immersed in 46.5 degrees C water. Distraction was provided by three different difficulty levels of continuous cognitive visual tasks. Experimental blocks consisted of test pain: (1) alone; 'baseline', (2) with conditioning pain; 'CPM', (3) with distraction; 'distraction' and (4) with conditioning pain and distraction; 'combined'. They were randomized and repeated three times and pain intensity and unpleasantness rated. Results showed an overall effect of experimental block on test pain intensity (P=0.0125). Post-hoc tests revealed a significant reduction in pain intensity ratings under Combined (21.2+/-2.3; mean+/-SEM) compared to CPM alone (16.0+/-2.3) (P

Trigeminal neuralgia (TN) is a rare neuropathic facial pain disorder. Two forms of TN, classical TN (CTN) and atypical TN (ATN), are reported and probably have different aetiologies. The aim of the present study was to evaluate the functional integrity of the diffuse noxious inhibitory controls (DNIC) in (1) a group of patients with classical trigeminal neuralgia (CTN), (2) a group of patients with atypical trigeminal neuralgia (ATN), and (3) a group of healthy controls in order to determine if a descending pain modulation deficit could participate in the pathophysiology of TN pain. DNIC responses of 14 CTN patients, 14 ATN patients and 14 healthy controls were obtained by comparing thermode-induced facial heat pain scores before and after activating DNIC. DNIC was triggered using a standard counter-irritation paradigm (i.e., immersion of the arm in painfully cold water). General sensitivity to pain was also evaluated by measuring mechanical pain thresholds over 18 points located outside the trigeminal territory. Healthy participants and CTN patients showed a 21% and 16% reduction in thermode-induced pain following the immersion, respectively (all p-values.01), whereas ATN patients experienced no change (p=.57). ATN patients also had more tender points (mechanical pain thresholds4.0kg) than CTN and healthy controls (all p-values.05). Taken together, these results suggest that the underlying physiopathology differs between CTN and ATN and that a deficit in descending inhibition may further contribute to the pain experienced by patients with ATN.

Females with Irritable Bowel Syndrome (IBS) and Temporomandibular Disorder (TMD) are characterized by enhanced sensitivity to experimental pain. One possible explanation for this observation is deficiencies in pain modulation systems such as Diffuse Noxious Inhibitory Control (DNIC). In a few studies that used brief stimuli, chronic pain patients demonstrate reduced DNIC. The purpose of this study was to compare sensitivity to prolonged heat pain and the efficacy of DNIC in controls to IBS and TMD patients. Heat pain (experimental stimulus; 44.0-49.0 degrees C), which was applied to left palm, was continuously rated during three 30-s trials across three separate testing sessions under the following conditions: without a conditioning stimulus; during concurrent immersion of the right foot in a 23.0 degrees C (control); and during noxious cold immersion in a (DNIC; 8.0-16.0 degrees C) water bath. Compared to controls, IBS and TMD patients reported an increased sensitivity to heat pain and failed to demonstrate pain inhibition due to DNIC. Controls showed a significant reduction in pain during the DNIC session. These findings support the idea that chronic pain patients are not only more pain sensitive but also demonstrate reduced pain inhibition by pain, possibly because of dysfunction of endogenous pain inhibition systems.

Opioids can elicit unexpected changes in pain sensitivity, known as opioid-induced hyperalgesia (OIH). The aim of this study was to explore whether OIH exists in patients with chronic pain treated with oral opioids (OP) versus non-opioid (NOP) analgesics. The sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) were evaluated in 73 OP and 37 NOP treated patients. Pain threshold, intensity and tolerance in response to the cold pressor (1 degrees C) were measured. DNIC was tested by co-administrating conditioned heat stimulation (47 degrees C) to the left forearm and a conditioning stimulation of 12 degrees C for 30s to the right hand. The results showed no differences between the two groups in any of the cold pain measures. In contrast, the magnitude of DNIC was significantly larger in the NOP than in the OP treated patients (p=0.003). A gender based analysis showed a significant difference in DNIC between OP and NOP treated men only. However, a mixed model ANOVA demonstrated a significant effect of treatment (OP versus NOP) (F=5.928, p=0.017) rather than gender on DNIC. A regression analysis showed that opioid dosage and treatment duration had a significant negative effect on the magnitude of DNIC in OP treated men (beta=-2.175, p=0.036 and beta=-2.061, p=0.047, respectively). In conclusion, oral opioids usage for the treatment of chronic pain does not result in abnormal sensitivity to cold pain, but seems to alter pain modulation. The use of 'advanced' psychophysics tests such as evaluation of DNIC can help understanding the phenomenon of OIH.

Surgical and medical procedures, mainly those associated with nerve injuries, may lead to chronic persistent pain. Currently, one cannot predict which patients undergoing such procedures are 'at risk' to develop chronic pain. We hypothesized that the endogenous analgesia system is key to determining the pattern of handling noxious events, and therefore testing diffuse noxious inhibitory control (DNIC) will predict susceptibility to develop chronic post-thoracotomy pain (CPTP). Pre-operative psychophysical tests, including DNIC assessment (pain reduction during exposure to another noxious stimulus at remote body area), were conducted in 62 patients, who were followed 29.0+/-16.9 weeks after thoracotomy. Logistic regression revealed that pre-operatively assessed DNIC efficiency and acute post-operative pain intensity were two independent predictors for CPTP. Efficient DNIC predicted lower risk of CPTP, with OR 0.52 (0.33-0.77 95% CI, p=0.0024), i.e., a 10-point numerical pain scale (NPS) reduction halves the chance to develop chronic pain. Higher acute pain intensity indicated OR of 1.80 (1.28-2.77, p=0.0024) predicting nearly a double chance to develop chronic pain for each 10-point increase. The other psychophysical measures, pain thresholds and supra-threshold pain magnitudes, did not predict CPTP. For prediction of acute post-operative pain intensity, DNIC efficiency was not found significant. Effectiveness of the endogenous analgesia system obtained at a pain-free state, therefore, seems to reflect the individual's ability to tackle noxious events, identifying patients 'at risk' to develop post-intervention chronic pain. Applying this diagnostic approach before procedures that might generate pain may allow individually tailored pain prevention and management, which may substantially reduce suffering.

Descending modulation of pain can be demonstrated psychophysically by dual pain stimulation. This study evaluates in 31 healthy subjects the association between parameters of the conditioning stimulus, gender and personality, and the endogenous analgesia (EA) extent assessed by diffuse noxious inhibitory control (DNIC) paradigm. Contact heat pain was applied as the test stimulus to the non-dominant forearm, with stimulation temperature at a psychophysical intensity score of 60 on a 0-100 numerical pain scale. The conditioning stimulus was a 60s immersion of the dominant hand in cold (12, 15, 18 degrees C), hot (44 and 46.5 degrees C), or skin temperature (33 degrees C) water. The test stimulus was repeated on the non-dominant hand during the last 30s of the conditioning immersion. EA extent was calculated as the difference between pain scores of the two test stimuli. State and trait anxiety and pain catastrophizing scores were assessed prior to stimulation. EA was induced only for the pain-generating conditioning stimuli at 46.5 degrees C (p=0.011) and 12 degrees C (p=0.003). EA was independent of conditioning pain modality, or personality, but a significant gender effect was found, with greater EA response in males. Importantly, pain scores of the conditioning stimuli were not correlated with EA extent. The latter is based on both our study population, and on additional 82 patients, who participated in another study, in which EA was induced by immersion at 46.5 degrees C. DNIC testing, thus, seems to be relatively independent of the stimulation conditions, making it an easy to apply tool, suitable for wide range applications in pain psychophysics.

Temporal filtering of afferent information is an intrinsic component of the processing of numerous types of sensory information. To date, no temporal filtering mechanism has been identified for nociceptive information. The phenomenon of offset analgesia, the disproportionately large decrease in perceived pain following slight decreases in noxious thermal intensity, however, suggests the existence of such a mechanism. To test the hypothesis that a temporal filtering mechanism is engaged during noxious stimulus offset, subjects rated heat pain intensity while stimulus fall rates were varied from -0.5 to -5.0 degrees C/s. In the absence of a temporal filtering mechanism, pain intensity would be expected to decrease in direct proportion to the stimulus fall rate. However, psychophysical fall rates were considerably faster than stimulus fall rates, such that subjects reported no pain while stimulus temperatures were clearly within the noxious range (47.2 degrees C). In addition, paired noxious stimuli were presented simultaneously to determine if offset analgesia evoked by one stimulus could inhibit pain arising from a separate population of primary afferent neurons. Pain ratings were significantly lower than those reported from two constant 49 degrees C stimuli when offset analgesia was induced proximal to, but not distal to, a second noxious stimulus. These asymmetric spatial interactions are not readily explained by peripheral mechanisms. Taken together, these findings indicate that offset analgesia is mediated in part by central mechanisms and reflect a temporal filtering of the sensory information that enhances the contrast of dynamic decreases in noxious stimulus intensity.

Provoked vestibulodynia is a common cause of superficial dyspareunia in young women. Recent evidence has pointed out the importance of studying endogenous pain modulation in these women. An impairment of diffuse noxious inhibitory controls (DNIC) has been suggested in chronic pain conditions with a female predominance such as fibromyalgia and temporomandibular disorder. Our aim was to examine whether patients with provoked vestibulodynia and healthy women with or without combined oral contraceptives (COC) display a DNIC response to cold noxious stimulation. Twenty patients with provoked vestibulodynia not using COC, 20 healthy women on COC and 20 healthy women without COC were included and tested days 7-11 of their menstrual cycle. Pressure pain thresholds (PPTs) and pain ratings using VAS were measured on the arm and leg before and during a cold pressor test. A socio-medical questionnaire, the Hospital and Anxiety Depression Scale and the Short Form-36 were completed. The majority of the subjects in all three study groups significantly increased their PPTs during cold noxious stimulation indicating a DNIC response. The patients displayed lower PPTs compared to the healthy women. Depression, anxiety and bodily pain were more often reported by the patients. No differences related to the intake of COC were observed between the healthy women. In conclusion, women with provoked vestibulodynia as well as healthy women irrespective of COC status display a DNIC response indicating an endogenous pain inhibition. However, the results imply a systemic hypersensitivity in women with vestibulodynia with low general pain thresholds as compared to healthy women.

Evidence has been accumulated suggesting that a dysfunction in pain inhibitory systems, i.e. in 'diffuse noxious inhibitory controls' (DNIC)-like mechanisms, might be-amongst other factors-responsible for the development of anatomically generalized chronic pain like fibromyalgia. The aim of the present study was to look for similar impairments in chronic tension-type headache (CTTH) as a regionally specific pain syndrome. Twenty-nine CTTH patients and 25 age- and sex-matched healthy control subjects participated in the study. After baseline assessment of electrical detection and pain thresholds, tonic heat stimuli were concurrently applied by a thermode to the thigh to induce DNIC-like pain inhibition. Tonic heat stimuli were applied either slightly above ('pain' condition) or slightly below ('heat' condition) pain threshold. For determination of electrical detection and pain thresholds, electrocutaneous stimuli were administered either to the forearm (extra-cranial site) or to the temple (cranial site), using a multiple staircase procedure. The increase in the electrical detection and pain thresholds induced by concurrent tonic heat stimulation was significantly smaller in the CTTH patients than in the control subjects. This group difference was present during the 'pain' as well as the 'heat' condition. Furthermore, the electrical detection and pain thresholds were affected in this group-specific manner both at the forearm and at the temple. These findings suggest that patients with CTTH suffer from deficient DNIC-like pain inhibitory mechanisms in a similar manner, as do patients with anatomically generalized chronic pain like fibromyalgia.

The aims of this study were to investigate possible sex differences in (a) intraoral pain evoked by topical application of capsaicin to the gingiva, and (b) the modulation of this pain by diffuse noxious inhibitory controls (DNIC). Three groups with a total of fifty-four healthy volunteers (20 men, 20 women using oral contraceptives (W+OC), 14 women not using (W-OC)) completed the study. In two sessions, intraoral pain was evoked by topical application of 30microL 5% capsaicin to the gingiva. Conditioning stimuli were applied with three min hand immersion in ice water in one session and 30 degrees C water (control) in another session. The capsaicin-evoked pain and the water-evoked pain were evaluated by the participants on visual analogue scales (VAS). No main effects of group in capsaicin-evoked pain (P>0.062) or water-evoked pain (P>0.149) were found. There was a significant group x time interaction (P

Vagal stimulation inhibits systemic pain perception in animals, probably via the nucleus tractus solitarius and its connections with descending nuclei in the brainstem which inhibit pain. Pain-inhibiting effects of such stimulation in humans, obtained from epileptic patients treated by vagal stimulation, are controversial. The aim of our study was to evaluate whether vagal stomach afferent activation inhibits pain perception in healthy humans. Pain thresholds, magnitude of tonic heat pain at 46 degrees C stimulation, pain temporal summation and laser pain evoked potentials were measured at the hand before and immediately after rapid drinking of 1500 ml water in 31 volunteers. We found an increase in heat pain threshold from 43.3+/-2.6 to 44.7+/-2.2 degrees C, P

Little is known about sex differences in the temporal pattern of descending inhibitory mechanisms, such as descending noxious inhibitory control (DNIC). Sex differences in temporal characteristics of DNIC were investigated by measuring pressure pain thresholds (PPTs) over time in the trapezius muscles (local pain areas) and the posterolateral neck muscles (referred pain areas) following repeated bilateral injection of hypertonic versus isotonic saline into both trapezius muscles. Ten females and 11 males received two consecutive bilateral injections, with 15 min interval, of either 5.8% hypertonic saline (0.5 ml in each side for each bilateral injection) or isotonic saline as a control in a randomized manner. Following hypertonic saline injection, the maximal pain intensities of the first and second bilateral injections were significantly higher in females than in males. The PPTs in the trapezius muscles were significantly lower in females than in males. Significantly higher PPTs (hypoalgesia) in men than in women were shown 15 min after the first bilateral injection, and 7.5 and 15 min after the second bilateral injection in the referred pain areas. Importantly, the second bilateral injection failed to further increase the PPTs for both sexes. These results showed that there were sex differences in temporal characteristics of descending inhibition with long-lasting hypoalgesia in men than in women. Repeated noxious muscular stimuli may inhibit further build-up of DNIC, which may reflect a mechanism of plasticity of the descending inhibitory systems following recurrent nociceptive barrage for both sexes.

The 'nociceptive' blink reflex is a method of examining human trigeminal pain pathways. We explored temporal summation of this reflex by using a train of pulses, rather than a single pulse, and remote activation of diffuse noxious inhibitory control (DNIC), to improve reliability, flexibility and nociceptive specificity of this technique. The R2 component of the nociceptive blink reflex response (nR2) was assessed in 28 healthy volunteers using between 1 and 7 pulses per stimulus train (inter-pulse interval 5 ms). The effect of DNIC on single-, double-, and triple-pulse nR2 was investigated. Compared to single pulses, double and triple pulses increased the sensation of pain, reduced the tactile and pain thresholds, and facilitated the blink reflex responses (reduced onset latency, increased magnitude and persistence of nR2). The maximal reflex facilitation was achieved using a triple pulse. Higher pulse numbers had no additional facilitatory effect. Activation of the DNIC system using heterotopic pain suppressed the nR2 evoked by double and triple stimulation by 16 and 42%, respectively, but not the nR2 from a single pulse. Stimulation with double and triple pulses may be more suitable to study influences on nociceptive pathways than single pulses and may widen the methodological flexibility of the nociceptive blink reflex technique. This technique may be useful in studying the trigeminal nociceptive system with particular reference to primary headache disorders and their neuropharmacology.

Laboratory pain research has been criticized as being irrelevant to the clinical experience of pain. Previous findings have been inconsistent with some studies suggesting that experimental pain responses may be related to the reported presence or severity of chronic pain, while others report no such associations. However, few of these studies assess a variety of laboratory pain responses, and none has assessed relationships between clinical pain and diffuse noxious inhibitory controls (DNIC) in healthy subjects. We administered questionnaire measures of pain, quality of life, and psychological variables to a sample of healthy adults participating in a laboratory study of age differences in pain responses. DNIC was not related to other laboratory pain responses, psychological variables, or physiological variables measured in the present study. Regression models predicting health-related quality of life (e.g. pain, physical functioning) revealed that age, sex, and DNIC responses explained between 10 and 25% of the variance in these dependent measures. Of the laboratory pain variables, only DNIC was the sole consistent predictor of clinical pain and physical health, with greater DNIC responses related to less pain, better physical functioning, and better self-rated health. In addition, age differences in DNIC appeared to partially mediate age differences in physical functioning. These findings highlight the potential clinical relevance of experimental pain procedures and suggest that DNIC may be the laboratory pain response most closely associated with clinical pain and health-related variables.

Recent clinical studies showed that acute migraine attacks are accompanied by increased periorbital and bodily skin sensitivity to touch, heat and cold. Parallel pre-clinical studies showed that the underlying mechanism is sensitization of primary nociceptors and central trigeminovascular neurons. The present study investigates the sensory state of neuronal pathways that mediate skin pain sensation in migraine patients in between attacks. The assessments of sensory perception included (a) mechanical and thermal pain thresholds of the periorbital area, electrical pain threshold of forearm skin, (b) pain scores to phasic supra-threshold stimuli in the same modalities and areas as above, and (c) temporal summation of pain induced by applying noxious tonic heat pain and brief trains of noxious mechanical and electrical pulses to the above skin areas. Thirty-four pain-free migraine patients and 28 age- and gender-matched controls were studied. Patients did not differ from controls in their pain thresholds for heat (44+/-2.6 vs. 44.6+/-1.9 degrees C), and electrical (4.8+/-1.6 vs. 4.3+/-1.6 mA) stimulation, and in their pain scores for supra-threshold phasic stimuli for all modalities. They did, however, differ in their pain threshold for mechanical stimulation, just by one von Frey filament (P=0.01) and in their pain scores of the temporal summation tests. Increased summation of pain was found in migraineurs for repeated mechanical stimuli (delta visual analog scale (VAS) +2.32+/-0.73 in patients vs. +0.16+/-0.83 in controls, P=0.05) and repeated electrical stimuli (delta VAS +3.83+/-1.91 vs -3.79+/-2.31, P=0.01). Increased summation corresponded with more severe clinical parameters of migraine and tended to depend on interval since last migraine attack. The absence of clinically or overt laboratory expressed allodynia suggests that pain pathways are not sensitized in the pain-free migraine patients. Nevertheless, the increased temporal summation, and the slight decrease in mechanical pain thresholds, suggest that central nociceptive neurons do express activation-dependent plasticity. These findings may point to an important pathophysiological change in membrane properties of nociceptive neurons of migraine patients; a change that may hold a key to more effective prophylactic treatment.

Diffuse noxious inhibitory control (DNIC) is part of a central pain modulatory system that relies on spinal and supraspinal mechanisms. Previous studies have shown that fibromyalgia (FMS) patients are lacking DNIC effects on experimental pain, compared to normal control (NC) subjects. Because DNIC has a greater effect on second pain than on first pain, we hypothesized that wind-up (WU) of second pain should be attenuated by a strong conditioning stimulus. Thus, we compared DNIC's effect on WU in three groups of subjects: 11 NC males, 22 NC females, and 11 FMS females. To separately assess the contributions of distraction related mechanisms to inhibition of second pain, we designed the experiment in such a way that directed the subjects' attention to either the test or conditioning stimulus. Repeated heat taps to the thenar surface of the right hand were used as test stimuli to generate WU of second pain. Immersion of the left hand into a hot water bath was the conditioning stimulus. As previous experiments have shown, DNIC requires a strong conditioning stimulus for pain attenuation, which may be at least partly dependent on a distraction effect. DNIC significantly inhibited thermal WU pain in normal male subjects, but adding distraction to the DNIC effect did not increase the extent of this inhibition. In contrast, neither DNIC nor DNIC plus distraction attenuated thermal WU pain in female NCs. DNIC plus distraction but not DNIC alone produced significant inhibition of thermal WU pain in female FMS patients. Our results indicate that DNIC effects on experimental WU of second pain are gender specific, with women generally lacking this pain-inhibitory mechanism.

The spinothalamic tract (STT) is a major ascending nociceptive pathway, interruption of which by cordotomy is used for pain relief, whereas the dorsal column (DC) pathway is usually not considered to be involved in pain transmission. However, recent clinical studies showed good relief of visceral pain in cancer patients after a DC lesion. Electrophysiological recordings in animals suggest that the analgesic effect is due to interruption of axons ascending from postsynaptic dorsal column (PSDC) neurons located in the vicinity of the central canal. In this behavioral study, we used a decrease in exploratory activity in rats after a noxious stimulus as an indicator of perceived pain, independent of withdrawal reflexes. Intradermal capsaicin injection almost abolished exploratory activity in naïve animals or in rats after a DC lesion, but did not change it in rats after ipsilateral dorsal rhizotomy or a lesion of the lateral funiculus on the side opposite to the injection. In contrast, a bilateral DC lesion counteracted the decrease in exploratory activity induced by noxious visceral stimuli for at least 180 days after the surgery. Although neurons projecting in both the STT and the PSDC path can be activated by noxious stimuli of cutaneous or visceral origin, our results suggest that the STT plays a crucial role in the perception of acute cutaneous pain and that the DC pathway is important for transmission of visceral pain.

Diffuse noxious inhibitory controls (DNIC), which involve supraspinal structures and modulate the transmission of nociceptive signals, were investigated in rats with chronic constriction injury of the sciatic nerve. Nerve-injured rats with increased sensitivity to mechanical and thermal stimulation on the operated side were anesthetized and recordings were made from trigeminal convergent neurons. Inhibitions of C-fiber-evoked neuronal responses during and after the application of nociceptive conditioning stimuli to the hindpaw, were measured to evaluate DNIC. The conditioning stimuli consisted of graded natural (pressure and heat) and electrical stimuli and were applied alternately to non-operated and operated hindpaws. Compared with the non-operated paw, inhibitions elicited by pressure on the operated hindpaw were increased significantly at all stimulus intensities. Albeit to a lesser extent, inhibitions elicited by thermal stimulation of the operated paw were also increased in the nerve-injured animals. Such exacerbation of DNIC-induced inhibitions produced by mechanical and thermal stimulation of the operated paw can be explained by an increase in the afferent input to the spinal cord. In contrast to the results obtained with natural stimulations, inhibitions evoked from the operated and non-operated paws were similar when graded electrical stimulation was used as the conditioning stimulus. This was true regardless of the intensity and frequency of stimulation and regardless of whether the stimuli were applied transcutaneously or directly to the sciatic nerve. The clear-cut difference between the results obtained with natural and electrical conditioning stimuli suggests that the nociceptive neurons involved in the triggering of DNIC may not be sensitized at the central level. Peripheral mechanisms such as the sensitization of nerve injured fibers and/or sprouting of nerve terminals may thus be the main causes of DNIC increase in this model of neuropathic pain.

Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30 mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P

'Diffuse noxious inhibitory controls' or DNIC is the inhibition of multireceptive neurons in the dorsal horn of the spinal cord that results when a noxious stimulus is applied to a region of the body remote from the neuron's excitatory receptive field. Although this phenomenon is well-documented, the behavioral consequences of DNIC are not clear. The present study was undertaken to determine how nocifensor withdrawal reflexes evoked by a noxious stimulus are altered by application of a second noxious stimulus to a distant part of the body. The tail flick or hindpaw withdrawal reflex of lightly anesthetized (0.6-1.0% halothane) rats was measured before, during and after another appendage was placed in water ranging in temperature from 45 to 54 degrees C. When the forepaw or hindpaw was placed in water exceeding 49 degrees C the tail flick reflex to acute noxious radiant heat was inhibited. In contrast, noxious conditioning stimuli, regardless of temperature or location, had no effect on the latency for hindpaw withdrawal evoked by an acute noxious stimulus, but did produce a change in reflex topography from flexion to extension. These results, along with previous research on DNIC, suggest that intense noxious stimuli: (1) inhibit the tail flick reflex via inhibition of multireceptive neurons in the dorsal horn; (2) disinhibit hindpaw extensor motoneurons by inhibiting the activity of multireceptive neurons involved in hindlimb flexion; and (3) reduce pain sensation by inhibiting multireceptive neurons projecting to the brain (see Model in Discussion).

In cluster headache (CH), pathogenesis has been emphasized the role of the posterior hypothalamus. It is part of a supraspinal network involved in the descending control of pain, including the diffuse noxious inhibitory control (DNIC), which in turn modulates the pain processing. We hypothesized that CH during the active phase facilitated temporal pain processing supported by abnormal functioning of the DNIC. We studied the functional activity of the DNIC by evaluating the effect of the cold pressor test (CPT) on the temporal summation threshold (TST) of the nociceptive withdrawal reflex. Ten subjects with episodic CH (2 women, 8 men) and 10 healthy subjects were recruited. Each subject underwent neurophysiological evaluation (nociceptive withdrawal reflex TST and related painful sensation) at baseline, then before (control session), during (pain session), and 5 min after (aftereffect) the CPT (immersing hand in a 4°C water bath for 4-5 min). Patients had been studied during both the active and remission phases. During the active phase, CH revealed a significant facilitation in temporal processing of pain stimuli (reduction of TST), which reverted during the remission phase. The CPT activating the DNIC did not produce any significant inhibitory effect of pain responses in CH during the active phase, whereas it induced a clear inhibition during the remission phase. We hypothesized that in CH, a dysfunction of the supraspinal control of pain related to the clinical activity of the disease, possibly supported by an abnormal hypothalamic function, leads to a facilitation in pain processing and a predisposition to pain attacks.

Reflex responses and neuronal excitation elicited by noxious stimuli applied to a given body site can be inhibited by application of noxious stimulation to another, even distant body region. Such heterotopic noxious stimulation (HNS) has been proposed to act via ‘diffuse noxious inhibitory controls’ (DNIC) which involve supraspinal components. The so-called on-cells of the rostral ventromedial medulla (RVM) in rats are thought to facilitate nociceptive transmission. Experimental manipulations that inhibit on-cells also inhibit withdrawal reflexes and nociceptive thalamic responses. In the present study on-cell activity was recorded in relation to the tail flick (TF) elicited by noxious heat applied to the tail both before and during either immersion of a paw in water above 56°C or application of strong pinch to various body regions. Such HNS elicited strong activation of on-cells, followed by depression even when HNS continued. When this depression was intense, tail-heating failed to elicit vigorous on-cell firing, and TF was retarded or abolished. These results are compatible with the hypothesis that antinociception elicited by HNS involves depression of on-cell firing and hence lack of facilitation of nociceptive transmission.

Behavioral and electrophysiological studies have shown that a noxious stimulus applied to one part of the body can reduce the response to a subsequent noxious stimulus elsewhere on the body. This phenomenon is referred to as diffuse noxious inhibitory controls (DNIC). In the present study we used immunocytochemical labeling for the Fos protein product of the c-fos proto-oncogene to determine the location of lumbar spinal nociresponsive neurons that are inhibited by a spatially remote noxious stimulus. Repetitive hindpaw pinch evoked pronounced Fos-like immunoreactivity in the superficial and deep laminae of the lumbar spinal cord. Placing the tail in 50 degrees C water before each hindpaw pinch significantly reduced Fos-like immunoreactivity in these regions. These data demonstrate that nociresponsive neurons in both the superficial and deep laminae of the spinal cord are sensitive to inhibition by a spatially remote noxious conditioning stimulus.