Hyperglycaemia and central obesity disrupt conditioned pain modulation: A single-blind cross-over randomised controlled trial.

Hyperglycaemia and high adiposity are risk factors for pain in diabetes. To clarify these links with pain, the effects of a glucose load on sensory detection, pain sensitivity, conditioned pain modulation (primary aims), and autonomic and endothelial functions (secondary aims) were examined in 64 pain-free participants: 22 with normal adiposity (determined by dual-energy X-ray absorptiometry), 29 with high adiposity, and 13 with combined high adiposity and elevated glycated haemoglobin (HbA1c; including prediabetes and type 2 diabetes). Participants ingested either 37.5-g glucose or 200-mg sucralose (taste-matched) in the first session and crossed over to the other substance in the second session one month later. At baseline, painful temple cooling (the conditioning stimulus) inhibited pressure- and heat-pain in the ipsilateral arm (the test stimuli) immediately after cooling ceased (partial η2's >.32). Glucose ingestion weakened pressure-pain inhibition irrespective of HbA1c levels (partial η2 =.11). However, a larger reduction in pressure-pain inhibition after ingesting glucose was associated with a higher waist/hip ratio (r =.31), suggesting a role of central obesity. Heat-pain inhibition was absent at baseline in unmedicated participants with elevated HbA1c, and these participants reported more occlusion-induced pain after ingesting glucose (partial η2's >.17). Glucose ingestion interfered with parasympathetic activity in all participants (partial η2 =.11) but did not affect endothelial function (measured by reactive hyperaemia) or alter other sensations (e.g., feet vibration detection). The disruptive effect of hyperglycaemia on conditioned pain modulation increases in line with central obesity, which might facilitate pain in diabetes. PERSPECTIVE: Ingesting 37.5-g glucose (approximately 350-mL soft drink) interfered with pain modulation in pain-free adults with normal adiposity or with combined high adiposity and HbA1c levels. The interference was stronger alongside increasing central obesity, suggesting that controlling blood glucose and body fat mass might help preserve pain modulation.

Temple cooling increases parasympathetic activity and decreases pressure pain on the hand.

BACKGROUND: Applying an ice cube to the temple (the conditioning stimulus) inhibits electrically evoked pain in the forearm. The present study aimed to determine whether temple cooling also inhibits pressure- and heat-pain test stimuli in the upper limb and, if so, to investigate the intra-session test-retest reliability of this response. Additional aims were to establish whether pain inhibition evoked by temple cooling was associated with parasympathetic activity; and to explore sex differences in response. METHODS: The sample consisted of 40 healthy adults (24 females). Heart rate was recorded continuously throughout the session. An ice cube (3 × 4 cm contact area) was applied for 1 min to the temple on the dominant side. Before and immediately afterwards, the pressure pain threshold was measured from the dorsal hand and sensitivity to heat (individually adjusted at baseline to elicit moderate pain) was measured from the ventral forearm. The procedures were repeated 15 min later. RESULTS: Temple cooling inhibited pressure pain on the hand but not heat pain on the forearm. However, test-retest reliability of pressure pain inhibition was poor. Heart rate decreased during temple cooling, consistent with a "diving" reflex. Males had stronger pressure pain inhibition, lower heart rate and higher overall autonomic activity than females. However, cardiac parasympathetic activation during temple cooling was comparable in both sexes and was unrelated to pain inhibition. CONCLUSIONS: These findings indicate that temple cooling evokes pain inhibition that is stronger in males than in females. Cardiac parasympathetic activity does not appear to mediate this response. SIGNIFICANCE: The conditioning stimulus in the conditioned pain modulation paradigm is often applied to the upper or lower limbs. This may confound pain-inhibitory effects in people with peripheral neuropathy who typically have enhanced or diminished sensation in the extremities. Applying an ice cube at the temple area induces pain-inhibitory effects on the upper limb after the ice is removed. Future research examining pain modulation in people with peripheral neuropathy may consider adopting temple cooling as the conditioning stimulus.

High Blood Glucose and Excess Body fat Enhance Pain Sensitivity and Weaken Pain Inhibition in Healthy Adults: A Single-blind Cross-over Randomized Controlled Trial.

To investigate links between blood glucose, body fat mass and pain, the effects of acute hyperglycaemia on pain sensitivity and pain inhibition were examined in healthy adults with normal (n = 24) or excess body fat (n = 20) determined by dual-energy X-ray absorptiometry. Effects of hyperglycaemia on heart rate variability and reactive hyperaemia were also explored. For the overall sample, ingesting 75-g glucose enhanced pain sensitivity during 1-minute cold-water immersion of both feet (conditioning stimulus) and weakened the pain inhibitory effect of cold water on pressure pain thresholds (test stimulus). Exploratory subgroup analyses not adjusted for multiple comparisons suggested that this effect was limited to people with excess fat mass. In addition, acute hyperglycaemia suppressed resting heart rate variability only in people with excess fat mass. Furthermore, regardless of blood glucose levels, people with excess fat mass had weaker pain inhibition for pinprick after cold water and reported more pain during 5-minutes of static blood flow occlusion. Neither high blood glucose nor excess body fat affected pinprick-temporal summation of pain or reactive hyperaemia. Together, these findings suggest that hyperglycaemia and excess fat mass interfere with pain processing and autonomic function. PERSPECTIVE: Ingesting 75-g glucose (equivalent to approximately 2 standard cans of soft drink) interfered with pain-processing and autonomic function, particularly in people with excess body fat mass. As both hyperglycaemia and overweight are risk factors for diabetes, whether these are sources of pain in people with diabetes should be further explored.

Anodal Transcranial Direct Current Stimulation Reduces Secondary Hyperalgesia Induced by low Frequency Electrical Stimulation in Healthy Volunteers.

The aim of the study was to determine whether transcranial direct current stimulation (tDCS) reduced pain and signs of central sensitization induced by low frequency electrical stimulation in healthy volunteers. Thirty-nine participants received tDCS stimulation under 4 different conditions: anodal tDCS of the primary motor cortex (M1), anodal tDCS of the dorsolateral prefrontal cortex (DLPFC), anodal tDCS over M1 and DLPFC concurrently, and sham tDCS. Participants were blind to the tDCS condition. The order of the conditions was randomized among participants. Pain ratings to pinpricks, the current level that evoked moderate pain, and pain induced by low frequency electrical stimulation were assessed in the forearm by an experimenter who was blind to the tDCS conditions. Anodal tDCS at M1 increased the current level that evoked moderate pain compared to sham and other conditions. Anodal tDCS of DLPFC completely abolished secondary hyperalgesia. Unexpectedly, however, concurrent anodal tDCS over M1 and DLPFC did not reduce pain or hyperalgesia more than M1 alone or DLPFC alone. Overall, these findings suggest that anodal tDCS over M1 suppresses pain, and that anodal tDCS over DLPFC modulates secondary hyperalgesia (a sign of central sensitization) in healthy participants. PERSPECTIVE: Anodal transcranial current stimulation (atDCS) at the left motor cortex and the dorsolateral prefrontal cortex increased the electrically-evoked pain threshold and reduced secondary hyperalgesia in healthy participants. Replication of this study in chronic pain populations may open more avenues for chronic pain treatment.

Painful diabetic peripheral neuropathy: Role of oxidative stress and central sensitisation.

AIMS: Diabetic peripheral neuropathy (DPN) occurs in about half of people with diabetes, of whom a quarter may develop chronic pain. Pain may remain for years yet be difficult to treat because the underlying mechanisms remain unclear. There is consensus that processing excessive glucose leads to oxidative stress, interfering with normal metabolism. In this narrative review, we argue that oxidative stress may also contribute to pain. METHODS: We reviewed literature in PubMed published between January 2005 and August 2021. RESULTS AND CONCLUSIONS: In diabetes, hyperglycaemia and associated production of reactive species can directly increase pain signalling and activate sensory neurons; or the effects can be indirect, mediated by mitochondrial damage and enhanced inflammation. Furthermore, pain processing in the central nervous system is compromised in painful DPN. This is implicated in central sensitisation and dysfunctional pain modulation. However, central pain modulatory function is understudied in diabetes. Future research is required to clarify whether central sensitisation and/or disturbances in central pain modulation contribute to painful DPN. Positive results would facilitate early detection and future treatment.

"Big girls don't cry": the effect of the experimenter's sex and pain catastrophising on pain.

OBJECTIVES: The expression of pain in males and females involves complex socio-psychological mechanisms. Males may report lower pain to a female experimenter to appear strong, whereas females may report higher pain to a male experimenter to appear weak and to seek protection. However, evidence to support these stereotypes is inconclusive. Individuals who catastrophise about pain rate higher pain than those who do not. How pain catastrophising interacts with the effect of the experimenter's sex on pain reports is yet to be explored. Thus, the aim of this study was to determine whether pain catastrophising moderated the effect of the experimenter's sex on pain reports in healthy males and females. METHODS: Participants (n=60, 30 males) were assigned to one of four experimental conditions: males tested by male experimenters, males tested by female experimenters, females tested by male experimenters, and females tested by female experimenters. Participants completed the Pain Catastrophising Scale, and then sensitivity to heat and to blunt (pressure-pain threshold) and sharp stimuli was assessed on both forearms, and to high frequency electrical stimulation (HFS) administered to one forearm. RESULTS: Females reported lower pressure-pain thresholds than males irrespective of the experimenters' sex. Females reported lower sharpness ratings to male than female experimenters only when the test stimuli were moderately or intensely sharp. Higher pain catastrophising scores were associated with higher sharpness ratings in females but not males. Additionally, higher pain catastrophising scores were associated with greater temporal summation of pain to HFS, and with lower pressure-pain thresholds in females who were tested by male experimenters. CONCLUSIONS: These findings indicate that the experimenters' sex and the participant's pain catastrophising score influence pain reports, particularly in females. Awareness of these psychosocial factors is important in order to interpret pain responses in a meaningful way, especially when females are tested by male experimenters. A greater awareness of sex/gender role biases and their potential interaction with pain catastrophising may help researchers and clinicians to interpret pain reports in meaningful ways. In turn, this may help to improve delivery of treatments for patients with chronic pain.

The Source of Hemisensory Disturbances in Complex Regional Pain Syndrome.

OBJECTIVES: In complex regional pain syndrome (CRPS), sensory deficits and/or hyperalgesia often extend beyond the affected limb to encompass other sites on the ipsilateral side of the body. The aim of this study was to determine whether hyperalgesia in the ipsilateral forehead reflects disinhibition and/or sensitization of trigeminal afferent or second-order neurons on the CRPS-affected side. PARTICIPANTS AND METHODS: To investigate this, blink reflexes to supraorbital electrical stimuli (a 2 mA triple pulse delivered using a concentric electrode) were recorded bilaterally in 30 CRPS patients and 20 controls of similar age and sex distribution. In addition, the effect of acoustic startle stimuli on pain and blink reflexes to supraorbital electrical stimuli was explored. RESULTS: Supraorbital electrical stimulation was more painful on the affected than unaffected side in patients (P<0.05), and was more painful on both sides in patients than controls (P<0.001). In addition, electrical stimulation of the ipsilateral forehead increased loudness and auditory discomfort to acoustic startle stimuli (P<0.05). However, blink reflexes were similar on both sides in patients, and smaller in amplitude and of longer latency in patients than controls (P<0.05). DISCUSSION: These findings suggest that trigeminal sensory nerve input activates sensitized and/or disinhibited nociceptive circuits in the thalamus or higher cortical centers in CRPS. This not only evokes ipsilateral supraorbital hyperalgesia but also compromises auditory perception. Hence, crosstalk between auditory and nociceptive signals at sites of convergence within the central nervous system may generate hyperacusis in CRPS.

Painful stimulation of a sensitized site in the forearm inhibits ipsilateral trigeminal nociceptive blink reflexes.

Exposure to moderate levels of ultraviolet B radiation (UVB) is painless but nevertheless induces an inflammatory response that sensitizes primary afferent nociceptors. Subsequently, heating the UVB-treated site can sensitize spinal nociceptors. We used a repeated-measures design to determine whether heating the UVB-treated site also triggers ipsilateral inhibitory controls. Specifically, a 2-cm diameter site on the forearm of 20 participants was exposed to UVB at twice the minimum erythema dose. 48 h later mechanical and thermal sensitivity had increased at the UVB-treated site, indicating primary hyperalgesia. In addition, sensitivity to blunt pressure had increased in the ipsilateral forehead, implying activation of an ipsilateral supra-spinal pro-nociceptive mechanism. Despite this, the area under the curve of the ipsilateral nociceptive blink reflex decreased when the UVB-treated site was heated to induce moderate pain. Together, these findings suggest that the UVB treatment sensitized primary nociceptive afferents and generated an ipsilateral supra-spinal pro-nociceptive mechanism. In addition, sensitization to heat induced by the UVB treatment strengthened an ipsilateral anti-nociceptive process elicited by heat-pain. Infrequent but enduring discharge of sensitized primary nociceptive afferents, driven by inflammation after UVB exposure, might initiate a lateralized supra-spinal pro-nociceptive influence that heightens awareness of impending harm on the sensitized side of the body. In addition, a lateralized anti-nociceptive response triggered by an intense barrage of nociceptive signals may help to differentiate stronger from weaker sources of pain.

Effect of combined opioid receptor and α2-adrenoceptor blockade on anxiety and electrically evoked startle responses.

The R3 component of the electrically evoked blink reflex may form part of a startle reaction. Acoustic startle responses are augmented by yohimbine, an α2-adrenoceptor antagonist that blocks α2-autoreceptors, and are potentiated by opioid receptor blockade. To investigate these influences on electrically evoked startle responses, 16 mg yohimbine, with (16 participants) or without 50 mg naltrexone (23 participants), was administered in separate double-blind placebo-controlled cross-over experiments. In each experiment, R3 (a probable component of the startle response) was examined before and after high-frequency electrical stimulation of the forearm, a procedure that initiates inhibitory pain controls. Anxiety and somatic symptoms were greater after yohimbine than placebo, and were potentiated by naltrexone. Pain ratings for the electrically evoked startle stimuli decreased after high-frequency electrical stimulation in the placebo session but remained stable after drug administration. Yohimbine with naltrexone, but not yohimbine alone, also blocked an inhibitory effect of high-frequency electrical stimulation on electrically evoked sharp sensations and R3. Together, the findings suggest that adding naltrexone to yohimbine potentiated anxiety and blocked inhibitory influences of high-frequency electrical stimulation on electrically evoked sensations and startle responses. Thus, opioid peptides could reduce activity in nociceptive and startle-reflex pathways, or inhibit crosstalk between these pathways. Failure of this inhibitory opioid influence might be important in chronically painful conditions that are aggravated by startle stimuli.

Involvement of Opioid Receptors and α2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study.

In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only evokes local signs of central sensitization but also triggers broader ipsilateral inhibitory influences on pain akin to a lateralized form of conditioned pain modulation. Paradoxically, some of these inhibitory influences are augmented by α2-adrenoceptor blockade. To determine whether opioid peptides mediate inhibitory effects after HFS, the opioid receptor antagonist naltrexone was coadministered orally with the α2-adrenoceptor antagonist yohimbine in 16 healthy women in a double-blind placebo-controlled crossover study. In each session, mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, pain ratings to electrical stimulation of HFS-treated or control sites in the forearm were assessed during and after painful stimulation of each temple. Unlike yohimbine alone, the naltrexone with yohimbine combination blocked analgesia evoked by HFS in the ipsilateral forehead to blunt pressure, and opposed the ipsilateral inhibitory effect of pain in the temple on electrically-evoked pain at the HFS-treated site in the forearm. These findings imply involvement of opioid peptides in an ipsilateral analgesic response that complements the more generalized form of conditioned pain modulation. Opioid mediation of this ipsilateral analgesic response appears to override opposing α2-adrenoceptor effects. PERSPECTIVE: HFS not only evokes local signs of central sensitization but also triggers a broader ipsilateral antinociceptive mechanism mediated by opioid receptors. Dysfunction of this lateralized pain modulation process might contribute to painful unilateral disorders such as migraine or complex regional pain syndrome.

Analgesia to pressure-pain develops in the ipsilateral forehead after high- and low-frequency electrical stimulation of the forearm.

In healthy participants, high-frequency electrical stimulation of the forearm not only evokes local hyperalgesia but also inhibits sensitivity to pressure-pain in the ipsilateral forehead, possibly due to activation of ipsilateral inhibitory pain modulation processes. The aim of this study was to compare the effects of high- and low-frequency electrical stimulation of the forearm on sensitivity to pressure-pain in the ipsilateral forehead, as inhibitory pain modulation may be stronger after low- than high-frequency electrical stimulation. Before and after high- and low-frequency electrical stimulation, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the electrically conditioned site in the forearm. In addition, sensitivity to blunt pressure was measured bilaterally in the forehead. Pain was more intense after high- than low-frequency electrical stimulation and was followed by primary and secondary hyperalgesia to mechanical stimulation after high- but not low-frequency electrical stimulation. Nevertheless, sensitivity to pressure-pain decreased to the same extent in the ipsilateral forehead after both forms of electrical stimulation. This decrease was associated with heightened sensitivity to pressure-pain at the electrically conditioned forearm site and with diminished sensitivity to heat around this site. These findings suggest that sensitisation of pressure-sensitive nociceptive afferents at the site of electrical stimulation is associated with generation of an ipsilateral pain-inhibitory process. This ipsilateral pain-inhibitory process may decrease sensitivity to pressure-pain in the ipsilateral forehead and suppress secondary hyperalgesia to heat.