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.     

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.     

Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients

The aim of this study was to evaluate the function of pain modulating systems subserving diffuse noxious inhibitory controls (DNICs) in primary headaches. DNICs were examined in 24 migraineurs, 17 patients with chronic tension-type headache (CTTH) and 20 healthy subjects by means of nociceptive flexion RIII reflex and the cold pressor test (CPT) as heterotopic noxious conditioning stimulation (HNCS). The subjective pain thresholds (Tp) and the RIII reflex threshold (Tr) were significantly lower in CTTH vs. controls. In controls a significant inhibition of the RIII reflex was observed during the CPT (-30%, P < 0.05). Conversely, migraine and CTTH patients showed facilitation (+31%, P < 0.05 and +40%, P < 0.01, respectively) of the RIII reflex during the HNCS. This study demonstrates a dysfunction in systems subserving DNICs in both migraine and CTTH. Impairment of endogenous supraspinal pain modulation systems may contribute to the development and/or maintenance of central sensitization in primary headaches.     

Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans

The aim of this study was to investigate the effects of diffuse noxious inhibitory controls (DNICs) on the temporal summation of the nociceptive flexion reflex (RIII reflex) in humans. Recordings were obtained from 36 healthy adults (16 M, 20 F), and the area and temporal summation threshold (TST) of the RIII reflex were measured. The subjective intensity of the painful sensation was rated on an 11-point visual analogue scale (VAS). Neurophysiological and VAS measurements were recorded after activation of DNICs by means of the cold pressor test (CPT), which involved immersing the hand in cold water (2-4 degrees C). A slight significant lower TST was found in the females versus the males. In all the subjects, the CPT induced a significant TST increase and RIII area reduction compared with the control session. The VAS results paralleled those of the RIII reflex area and TST. During the CPT, a significant difference in the percentage TST increase emerged between females and males, being lower in the former. Similarly, we found a significantly lower percentage reduction of the RIII area in women than in men during the CPT. To summarize, activation of DNICs through the CPT significantly increased the TST of the RIII reflex in healthy subjects. This inhibitory effect was gender-specific. Whereas other findings are based on psychophysical evaluations, the results of this experimental study provide an objective neurophysiological demonstration that DNICs attenuate temporal summation in humans and confirm the presence of significant differences in pain modulation mechanisms between men and women.     

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.     

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.     

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.     

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.     

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.     

NK1 receptor-expressing spinoparabrachial neurons trigger diffuse noxious inhibitory controls through lateral parabrachial activation in the male rat

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls, which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. The principal feature of DNIC is that they are subserved by a loop that involves supraspinal structures that have not yet been identified. Using behavioral, in vivo extracellular electrophysiological and anatomical approaches, we studied the neuronal network underlying DNIC. Using a new behavioral model of DNIC, in which facial grooming produced by formalin injection into the vibrissa pad is inhibited by a conditioning noxious stimulation, formalin injection into the hindpaw, we show that blockade of NK1 receptors in the lumbar spinal cord – by intrathecal administration of the NK1 receptor antagonist, RP67580 – largely attenuates DNIC-induced facial analgesia. In a second series of experiments, WDR neurons were recorded from the trigeminal subnucleus oralis and inhibited their C-fiber-evoked responses by the conditioning noxious heat stimulation of the hindpaw. We show that inactivating the lateral parabrachial area – by microinjecting the GABA_A agonist, muscimol – strongly attenuates DNIC-induced inhibition of C-fiber-evoked responses. Finally, our neuroanatomical tracing study demonstrates that the descending pathway for DNIC does not involve direct descending projections from the PB area. We conclude that (1) lamina I/III spinoparabrachial neurons that express the NK1 receptor and (2) parabrachial neurons are involved in the ascending part of the loop underlying DNIC and that the descending pathway for DNIC might include indirect projections to the spinal or medullary dorsal horn.     

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.     

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.     

A comparison of blogs by depressed men and women

This paper reports on a study comparing Internet blogs written by 45 men and 45 women who self-identified as depressed. Using qualitative and inductive methods, distinct differences among the male and female experiences of depression were documented. Among the most important differences were the distinctions male and female bloggers made in regards to (1) the bio-medicalization of depression; (2) the relative significance of world events as compared to relationships in depression experiences; and (3) violence, including suicide and cutting. Theoretical reasons and explanations for these findings are discussed.     

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.     

A comparison of suicide notes written by men and women

Previous research using small samples and subjective judgments has failed to identify reliable gender differences in suicide notes. Suicide notes written by 166 women and 513 men collected by Edwin Shneidman were analyzed by the Linguistic Inquiry and Word Count computer program. Six significant differences and four trends were identified. The suicide notes written by women had a higher percentage of words found in the dictionary, negations, words indicative of cognitive process, discrepancies and present tense verbs. The suicide notes of women seemed to have more content indicative of hopelessness, defeat-entrapment and falling short of internalized standards.