Indirect effects of intrathecal morphine upon diffuse noxious inhibitory controls (DNICs) in the rat

Diffuse noxious inhibitory controls (DNICs) affect all convergent neurones recorded in the dorsal horn of the spinal cord or the nucleus caudalis of the trigeminal system. They are triggered specifically by heterotopic noxious stimulation. DNICs acting at the trigeminal level were triggered by noxious thermal stimulation of caudal parts of the body, and the effects of intrathecal morphine applied at the coccygeal level were tested. The immersion of the right hind paw or of the tail induced inhibitions on C-fibre responses of trigeminal convergent neurones of 95.8 +/- 2.8% and 93.8 +/- 2.4+ respectively. Intrathecal morphine (15 micrograms; 20 microliters) produced an almost complete blockade of inhibitions triggered from the tail without significantly affecting those triggered from the hind paw. A reversal by systemic naloxone (0.4 mg/kg i.v.) was obtained in all cases. These results indicate that intrathecal morphine induced a segmental depression of nociceptive messages strong enough to prevent the spinal initiation of DNICs. We suggest that the segmental depression of nociceptive transmission induced by morphine led to a consequent blockade of DNICs acting on the whole population of convergent neurones not initially affected by the noxious stimulus. These findings are discussed with regard to the strong analgesic effects of intrathecal morphine observed in both behavioural and clinical studies.     

Diffuse noxious inhibitory control evoked by tonic craniofacial pain in humans

Tonic pain in one body segment can inhibit the perception of pain in another body segment. This phenomenon is mediated by diffuse noxious inhibitory controls (DNIC), and its efficacy in craniofacial regions is investigated in this study. A compressive device that evoked a tonic, moderate/severe, headache‐like, conditioning pain (～8/10 on a visual analogue scale) was applied for 15 min. Eleven males participated in the study. Pressure pain threshold (PPT) and pressure pain tolerance (PPTol) at multiple heterosegmental body sites (right masseter, splenius capitis, second intermediate phalange, brachioradialis and tibialis anterior) were measured before, during and at multiple time points (5, 20 and 35 min) after the termination of the conditioning pain. PPTs and PPTols were compared within participants across two experimental sessions; one that included painful conditioning stimulation, and a separate control session on a different day. Painful conditioning increased PPT significantly during pain over the masseter (p <0.05) and over the tibialis anterior (p <0.01). PPTol was unchanged. In the period after the painful conditioning stimulation PPT was depressed compared to control. This study shows that pain evoked from the craniofacial region evokes DNIC‐like mechanisms on segmental as well as heterosegmental sites.     

Gender differences in pain modulation by diffuse noxious inhibitory controls: A systematic review

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.     

Lack of sex differences in modulation of experimental intraoral pain by diffuse noxious inhibitory controls (DNIC)

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<0.001) with W+OC reporting lower capsaicin-evoked pain scores than W-OC in the early phase (2-3min) and lower pain scores than men in the later phase (5-11min). The degree of modulation by DNIC did not differ between groups (P=0.636). In conclusion, for a superficial type of intraoral pain, only minor sex differences were found in pain intensity and no differences in the degree of endogenous modulation by DNIC. Female sex and the use of OC may not consistently be associated with higher sensitivity to pain.     

Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients

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.     

Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis.

The purpose was to investigate the influence of ongoing pain from an inflammatory nociceptive pain with two different disease durations on somatosensory functions and the effect of heterotopic noxious conditioning stimulation (HNCS) on 'diffuse noxious inhibitory controls' (DNIC) related mechanisms. Eleven patients with rheumatoid arthritis of a short duration (<1 year) (RA1), and 10 patients with rheumatoid arthritis of longer duration (>5 years) (RA5) as well as 21 age- and sex-matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed over a painful and inflamed joint as well as in a pain-free area, i.e. the right thigh before HNCS (cold-pressor test) and repeated at the thigh only during and following HNCS. In RA1 and RA5 allodynia to pressure was seen over the joint (p<0.02 and p<0.001 respectively) in conjunction with hypoaesthesia to light touch (p<0.02) and hyperaesthesia to innocuous cold (p<0.05) in RA5. At the thigh, allodynia to pressure was found in RA5 (p<0.002). During HNCS, the sensitivity to pressure pain decreased in patients and controls alike (p<0.001). In conclusion, over an inflamed joint allodynia to pressure was found in both RA groups, with additional sensory abnormalities in RA5. In a non-painful area, allodynia to pressure was found in RA5, suggesting altered central processing of somatosensory functions in RA5 patients. The response to HNCS was similar in both RA groups and controls, indicating preserved function of DNIC-related mechanisms.     

Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses

Psychophysical experiments were carried out on 6 human subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4–8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51.5°C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Aδ and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Aδ heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of single Aδ heat nociceptive afferents, C polymodal nociceptive afferents, and “warm” afferents of rhesus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers ( ). These spinal cord summation mechanisms could account for the summation of second pain.     

Counterstimulation and pain perception: effects of electrocutaneous vs. auditory stimulation upon cold pressor pain

This study tested the hypothesis that distraction from a painful stimulus is best achieved by concurrent presentation of a similar stimulus. Specifically, it was hypothesized that pain perception would be interfered with, and thus reduced, when a stimulus similar to the sensory features of a painful stimulus was delivered concurrently. Subjects matched aversiveness thresholds for electrocutaneous or auditory stimulation so that both forms of stimulation could be judged to be subjectively of similar affective value. Subjects were then run in the cold pressor test for 2 min. While control subjects for each modality were not administered counterstimulation concurrently with cold pressor exposure, experimental subjects within each modality condition received concurrent counterstimulation. Magnitude estimation ratings of the aversiveness of counterstimulation were provided concurrently with cold pressor pain ratings, every 30 sec. The results indicated that, as predicted, subjects exposed to concurrent electrical stimulation produced lower pain ratings than subjects exposed to auditory stimulation and controls. In addition, a mutual interference effect between the cold pressor and the tactile counterstimulation was found: subjects also rated electrical stimulation as a less aversive than auditory stimulation over the duration of the cold pressor test.     

Chronic back pain, acute postoperative pain and the activation of diffuse noxious inhibitory controls (DNIC).

The effect of the presence of either chronic or acute clinical pain on pain threshold and on the nociceptive flexion reflex (RIII) threshold was studied. The experimental pain sensation and the flexion reflex were evoked by trains of short electrical pulses. It was hypothesized that both kinds of clinical pain would be able to induce 'diffuse noxious inhibitory controls' (DNIC) and thereby raise the 2 experimental thresholds. Patients with chronic low back pain, patients with postoperative pain from oral surgery, and pain-free subjects were tested in 3 conditions: during baseline, after i.v. administration of a placebo, and after i.v. administration of naloxone. In comparison with 2 pain-free control groups, the 2 pain groups had a significantly higher pain threshold in all conditions. However, the RIII threshold was not significantly elevated in chronic or acute pain patients compared to controls. Naloxone had no effect on the RIII or pain threshold in any of the groups. It is concluded that the increased pain threshold which is frequently found in chronic pain patients, and which could be confirmed in the present study, does not result from a DNIC effect. The adaptation level theory offers an alternative explanation. Also, the acute postoperative pain in this study did not seem to induce DNIC. Because other forms of acute pain have been found to be effective in activating DNIC, future research should establish which pains are and which pains are not effective.     

Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables

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.     

Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.

(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.     

An investigation of cold pressor pain in children (Part I)

Although the cold pressor model of pain has been used widely in laboratory studies with adults, it has been rarely used to study pain in children, likely because of obvious ethical concerns about the well-being of child participants. The goals of the present investigation were to determine (1) whether a laboratory study of this type could be conducted in a way that children would find interesting and non-threatening, and (2) whether potentially useful data could be gathered systematically within the framework of such a study. Results of a pilot study in children 6-12 years, with water temperature at 15 degrees C (n = 37) and 12 degrees C (n = 29), indicated that useful data could be obtained from this paradigm. Children's pain ratings increased with duration of arm immersion in the water and with decreasing water temperature. Most importantly, children and their parents perceived the format to be interesting and non-stressful. Continued caution and improved techniques for monitoring the well-being of child participants need to be a part of any future investigations of this type.     

Regional cerebral blood flow (rCBF) in man during perception of radiant warmth and heat pain

The present study concerns the effects of experimental pain (radiant warmth and heat pain) on regional cerebral blood flow (rCBF) in pretrained subjects. The radiant warmth caused a general rCBF increase. However, if anxiety was avoided, heat pain caused the general rCBF level to return towards the level at rest. Thus, pain sensation per se may not cause a larger rCBF (and metabolic) response than that of the localized tactile stimulation, provided that the element of psychic apprehension and anxiety is eliminated or controlled.     

Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia.

In patients with localized musculoskeletal pain, spread of pain and tenderness outside the primarily painful area and sometimes even generalization of pain have been reported, the latter possibly indicating a dysfunction of endogenous pain modulatory systems. The purpose of the study was to use patients with long-term trapezius myalgia as a model to investigate the possible influence of a localized muscle pain on somatosensory processing in a remote pain-free area and the effect of heterotopic noxious conditioning stimulation (HNCS) on 'diffuse noxious inhibitory controls' (DNIC) related mechanisms. Altered somatosensory processing may indicate subclinical derangement of endogenous modulatory systems. Ten patients with long-term (> or = 1 year) trapezius myalgia and 10 age- and sex-matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed at the right thigh before, during and following HNCS. Pain was induced in the forearm by the tourniquet test. At rest allodynia to pressure was found at the thigh in conjunction with hypoaesthesia to cold (p<0.03 and p<0.01 respectively), in patients compared with controls. During HNCS, the sensitivity to pressure pain and suprathreshold heat pain decreased in patients and controls alike (p<0.02 and p<0.04 respectively) and returned to baseline following HNCS. In conclusion, in a remote non-painful area allodynia to pressure and hypoaesthesia to cold were found in conjunction with preserved function of DNIC-related mechanisms. Whether altered central somatosensory processing at rest may indicate a predisposition for further spread of pain is at present unclear.     

Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults

Despite decades of research, hundreds of studies, and a number of recent reviews, the effects of aging on the experience of pain remain poorly understood. Many prior investigators have reported increases in persistent pain conditions and diminished tolerance for certain types of laboratory-induced pain among the elderly. While explanations for these effects often propose senescent decrements in endogenous analgesic systems as a possible contributory mechanism, almost no direct empirical evidence for this hypothesis has yet emerged in human studies. The present investigation was designed to evaluate the existence and nature of these putative age-related differences in endogenous pain inhibition. Groups of healthy younger (n=45, mean age=21.6 years, range=18-25) and older (n=48, mean age=63.1 years, range=55-67) adults participated in a controlled, two-session laboratory assessment of diffuse noxious inhibitory controls (DNIC), a measure of endogenous pain inhibition. In this study, we examined age differences in the effects of concurrent cold pain on ratings of heterotopically presented repetitive noxious thermal stimuli. Interestingly, older adults demonstrated facilitation rather than inhibition of thermal pain during concurrent noxious cold stimulation while younger adults demonstrated some expected DNIC effects (i.e. a reduction in thermal pain ratings during heterotopic stimulation with noxious cold). Collectively, the findings of the present study suggest age-associated decrements in at least one form of endogenous analgesic response. If replicated, such findings of reduced pain-modulatory capacity in the elderly may partially explain age-related differences in the prevalence, severity, and impact of chronic pain.     

The cold pressor pain paradigm in children: feasibility of an intervention model (Part II)

The purpose of this study was to examine the feasibility of testing a psychological approach (hypnosis) to pain reduction in children using the cold pressor paradigm. Children's pain ratings at 10 sec intervals and duration of arm immersion (40 sec maximum) in 15 degrees C (n = 37) and 12 degrees C water (n = 29) were assessed in 6-12-year-old children during 2 baseline trials (alternating arms), followed by 2 more trials after randomization to a control or hypnosis treatment condition. Hypnosis was found to reduce pain significantly more than the control condition in both 15 degrees C and 12 degrees C water. Hypnotic susceptibility was not strongly related to hypnotic pain reduction. However, age was significant, with younger children showing higher pain ratings and early arm withdrawal rates and less response to hypnosis than older children. In 15 degrees C water, females had higher pain ratings and early withdrawal rates than males, but this sex discrepancy disappeared in 12 degrees C water. This study demonstrated the feasibility of the cold pressor paradigm for testing intervention strategies and its potential for enhancing our understanding of pain in children.     

Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications.

(1) Diffuse noxious inhibitory controls (DNIC) were tested for their effect on noxious only, non-noxious and proprioceptive cells in the dorsal horn of the intact anaesthetized rat. Unlike convergent neurones, as described in the previous paper, there was no effect of DNIC on these neurones. It is concluded that convergent neurones are specifically inhibited by DNIC. (2) The effect of DNIC could not be demonstrated for convergent neurones in the spinal animal. Thus the neuronal substrate for DNIC must involve supraspinal structures. (3) Because of the level of firing in convergent neurones induced by hair and touch receptors, presumably constantly and randomly activated in the freely moving animal, a noxious message arriving at higher centres may be partly masked by this background noise. On the basis of the known role of convergent neurones in nociception, we propose the following mechanism which may interpret this paradoxical convergence: two pools of convergent neurones are influenced by a painful peripheral stimulation, one segmental pool being activated whilst the remaining population of cells is inhibited; the "contrast" between the messages from these two pools may well produce a significant pain signalling output from the convergent dorsal horn cells. (4) These results and their theoretical implications are discussed with regard to the concept of the "analgesic system", certain clinical observations and the paradoxical pain relieving effects of counterirritation and some forms of acupuncture.     

Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: diffuse noxious inhibitory controls in the trigeminal nerve territory.

The purpose of this study was to determine whether the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and pain intensity are inhibited by heterotopic ischemic stimulation. The tourniquet pressure with 50 mmHg greater than the individual's systolic pressure was applied to the left upper arm for 10 min as ischemic conditioning stimulation. The late component of SEP and visual analogue scale (VAS) were recorded at 4 times and both were significantly decreased when ischemic conditioning stimulation was applied. The maximum reductions in SEP amplitude and the VAS value were 26.1% and 21.2%, respectively, during ischemic conditioning stimulation. After-effect was observed 5 min after removal of the conditioning stimulation. The present study revealed that heterotopic ischemic stimulation attenuated the late component of SEP induced by electrical tooth stimulation, triggering diffuse noxious inhibitory controls (DNIC) and after-effects in the trigeminal nerve territory. It was also suggested that the DNIC effect differs, depending on the intensity, kind, and quality of the test and conditioning stimuli.     

Facilitation and inhibition of withdrawal reflexes following repetitive stimulation: electro- and psychophysiological evidence for activation of noxious inhibitory controls in humans.

A systematic evaluation of nociceptive withdrawal reflexes and pain rating was undertaken in order to explore the mechanisms underlying temporal summation of repetitive electrocutaneous stimulation in healthy individuals (n=12; age=27.5+/-1.5 years). Five-second subreflex threshold (RT) electrocutaneous stimulation at different frequencies (single stimulus, 5, 10, and 20 Hz) and intensities (0.6RT and 0.8RT) was applied on the dorsum of the foot, and the withdrawal reflex from the ipsilateral biceps femoris muscle was measured. The subjects scored the pain intensity on a visual analogue scale (0-100 mm) for the beginning, the middle and the end phase of the 5 s series of stimulation, and the respective averaged reflex size was calculated. The reflex size increased at stimulus frequencies 10 Hzx0.8RT and 20 Hzx0.8RT as compared with 5 Hzx0.8RT (SNK, P<0.05), and by an increase in current intensity from 0.6RT to 0.8RT (SNK, P<0.05). Pain intensity increased with the increase in the current intensity from 0.6RT to 0.8RT (SNK, P<0.05). Profound activation of inhibition following electrocutaneous pain stimuli was demonstrated by reduction in pain intensity and reflex size during the last second as compared with the first second at 0.6RT current intensity (SNK, P<0.05). The pain intensity peaked between 5 and 10 Hz (P<0.05) and was reduced at 20 Hz for current intensities at 0.8RT (P<0.05). This study provides evidence for both frequency dependent central integration of the repetitive electrocutaneous stimuli and activation of a pain inhibitory system by psychophysical and electrophysiological means, demonstrating the delicate balance between neuronal facilitation and inhibition in the human pain system.