Diffuse Noxious Inhibitory Controls Research Articles

Age- and Sex-Dependent Effects of Moderate Exercise on Endogenous Pain Inhibition in Rats.

Diffuse noxious inhibitory controls (DNICs), or the pain inhibits pain phenomenon, refer to reduced pain-like behaviors that are displayed following a noxious conditioning stimulus located far from the test stimulus and have also been referred to as "descending control of nociception" when measured in awake-behaving animals. In this study, we sought to determine the impact of moderate long-term exercise on the DCN response and determine if this effect differed across age and sex. After a six-week exercise program consisting of 30 min of moderate treadmill running 5 days a week, the animals' forepaws were injected with capsaicin, and DCN responses were assessed using thermal withdrawal latencies of the hind paw. Young, exercised male and female rats displayed prolonged DCN responses relative to their sedentary counterparts, with the young exercised male group displaying longer-lasting DCN facilitation than the young exercised females. Exercise did not impact DCN responses in either male or female aged rats. Additionally, the serum testosterone levels did not change following exercise in any group. Importantly, the levels of corticosterone did not change following the exercise program, indicating that changes in the DCN response are not due to stress-induced analgesia. Our findings suggest that moderate exercise can facilitate the DCN response in young animals, even when this exercise does not change the levels of serum testosterone.

μ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of μ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition. Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of μ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test. At 42 days of monoarthritis, μ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the μ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis. The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of μ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

A back-translational study of descending interactions with the induction of hyperalgesia by high-frequency electrical stimulation in rat and human.

In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development.

Association of Interoceptive Sensibility and Pain Psychophysics in Healthy Subjects and Chronic Pain Patients

Objective: Interoception is the sense of the physiological condition of the body; it results from the integration of somatic information, including pain, with visceral information. The aim of the study was to assess whether interoceptive sensibility and awareness modulate the perception of experimental pain in healthy participants and recurrent/chronic pain patients. Methods: To assess whether interoceptive sensibility and awareness modulate the effects of experimental noxious stimuli, pain-free subjects (N=52) and patients with recurrent (N= 47) and chronic pain (N= 42) underwent the following psychophysical tests: von Frey filaments (punctate mechanical threshold), pressure pain threshold, heat and cold pain threshold and tolerance, and diffuse noxious inhibitory control (DNIC). They also completed the Body Perception Questionnaire Short Form (BPQ-SF), which discriminates between sub- and supradiaphragmatic interoception, and the Multidimensional Assessment of Interoceptive Awareness I (MAIA I), which measures multiple dimensions of interoceptive sensibility/awareness. Results: After controlling for age and psychopharmacological treatment, a significant difference in heat pain tolerance among groups (F=3.16; p=.047; η2=.06) was found cancelled however by all BPQ dimensions and noticing of MAIA I. Conclusion: Different mechanism of experimental pain perception can be suggested in subjects with and without pain, based on the role of interoceptive sensibility.

Unmasked Neuropathic Pain After Neurectomy: A Case Series and Review of the Literature

Summary: Localization of neuropathic pain to a specific peripheral nerve origin relies on patient history, physical examination, and nerve blocks. Neurectomy of the involved nerve(s) can successfully alleviate patients’ pain. However, a subset of patients postoperatively describe persistent pain, but say that the pain “moved” to a new location (eg, from the dorsum of the foot to the lateral foot). This may be viewed as a treatment failure by the patient and surgeon alike. Further investigation, however, may localize the new pain to an additional, separate peripheral nerve injury, which was previously unrecognized by both parties. The mechanism involved is that of pain masking and unmasking. Successful treatment of the more prominent pain stimulus allows for recognition of a second, less-offending peripheral nerve injury. As the field of surgical treatment of chronic peripheral neuropathic pain advances, it is important to identify and define specific nuances of diagnosis and treatment via neurectomy. The term “diffuse noxious inhibitory control,” used to describe the pain-inhibits-pain pathway, may help explain the phenomenon of masking, whereby one pain generator is more prominent and shields another site from recognition and subsequent diagnosis. In this context, unmasked pain should be considered as a potential source of surgical treatment failure. We present a series of patients who, following improvement in the initial location of their pain, reported pain in a distinctly new peripheral nerve distribution, leading to reoperation.

Counterirritation by Pain Inhibits Responses to and Perception of Aversive Loud Tones.

The application of a noxious stimulus reduces the perception of other noxious stimuli, which can be assessed by an experimental method called "counterirritation." The question arises whether this type of inhibition also affects the processing of other aversive (but not nociceptive) stimuli, such as loud tones. If aversiveness or, in other words, negative emotional valence qualifies a stimulus to be affected by counterirritation, the general emotional context may also play a role in modulating counterirritation effects. We involved 63 participants in this study (M age = 38.8, SD = 10.5 years; 33 males, 30 females). We tried to counterirritate their perceptual and startle reactions to aversively loud tones (105 db) by immersing the hand into a painful hot water bath (46°C) in two emotional valence conditions (i.e., a neutral and a negative valence block in which we showed either neutral pictures or pictures of burn wounds). We assessed Inhibition by loudness ratings and startle reflex amplitudes. Counterirritation significantly reduced both loudness ratings and startle reflex amplitudes. The emotional context manipulation did not affect this clear inhibitory effect, showing that counterirritation by a noxious stimulus affects aversive sensations not induced by nociceptive stimuli. Thus, the assumption that "pain inhibits pain" should be widened to "pain inhibits the processing of aversive stimuli." This broadened understanding of counterirritation leads to a questioning of the postulate of clear pain specificity in paradigms like "conditioned pain modulation" (CPM) or "diffuse noxious inhibitory controls" (DNIC).

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. To assess the descending diffuse noxious inhibitory control in RLS patients. Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 μV; HC, 10.1 μV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Effect of Voluntary Exercise on Endogenous Pain Control Systems and Post-traumatic Headache in Mice

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PerspectiveThis article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI.

Treatment of Knee Osteoarthritis with Transcutaneous Electrical Nerve Stimulation

In China, the majority of osteoarthritis patients have the disease in the knee. Clinically, knee osteoarthritis (KOA) often has joint swelling, pain, stiffness, dysfunction and other symptoms, which reduce the patients’ quality of life. There is a trend that osteoarthritis affects more and more young people in China, so it is much more important to treat KOA. Being a cheap and non-surgical option, the transcutaneous electrical nerve stimulation (TENS) has unique advantages in dealing with the pain caused by KOA. This article presents the pathogenesis and pain mechanism of KOA, describes the mechanism of TENS in KOA treatment, discusses the advantages and disadvantages, and proposes some combined treatment methods. Some studies have shown that the pathogenesis of KOA is related to the theory of unequal settlement of knee joints, and the pain comes from cartilage, subchondral bone and synovial membrane lesions. The gate control theory, endogenous opioid peptide release theory and diffuse noxious inhibitory controls theory are considered as the theoretical basis for TENS to inhibit pain. Its effectiveness, adaptability and incidence of adverse reactions are better than using drugs, but it cannot improve walking ability and the range of motion of the joints. Combination therapies of TENS are currently effective for treating KOA, including TENS combined with ultrasound, sodium hyaluronate, massage, functional training and other treatment options.

A critical brainstem relay for mediation of diffuse noxious inhibitory controls.

The CNS houses naturally occurring pathways that project from the brain to modulate spinal neuronal activity. The noradrenergic locus coeruleus (the A6 nucleus) originates such a descending control whose influence on pain modulation encompasses an interaction with a spinally projecting non-cerulean noradrenergic cell group. Hypothesizing the origin of an endogenous pain inhibitory pathway, our aim was to identify this cell group. A5 and A7 noradrenergic nuclei also spinally project. We probed their activity using an array of optogenetic manipulation techniques during in vivo electrophysiological experimentation. Interestingly, noxious stimulus evoked spinal neuronal firing was decreased upon opto-activation of A5 neurons (two-way ANOVA with Tukey post hoc, P < 0.0001). Hypothesizing that this may reflect activity in the noradrenergic diffuse noxious inhibitory control circuit, itself activated upon application of a conditioning stimulus, we opto-inhibited A5 neurons with concurrent conditioning stimulus application. Surprisingly, no spinal neuronal inhibition was observed; activity in the diffuse noxious inhibitory control circuit was abolished (two-way ANOVA, P < 0.0001). We propose that the A5 nucleus is a critical relay nucleus for mediation of diffuse noxious inhibitory controls. Given the plasticity of diffuse noxious inhibitory controls in disease, and its back and forward clinical translation, our data reveal a potential therapeutic target.

Diffuse noxious inhibitory controls in chronic joint inflammatory Pain: Study of the descending serotonergic modulation mediated through 5HT3 receptors

The loss of diffuse noxious inhibitory controls (DNIC) is recognized as a predictor of chronic pain. Mechanistically, DNIC produces analgesia by a heterotopically applied conditioning-noxious stimulus (CS) and yet underexplored descending modulatory inputs. Here, we aimed at studying DNIC in monoarthritis (MA) by exploring the spinal component of the descending serotonergic system, specifically 5-hydroxytryptamine 3 receptors (5-HT3R).MA was induced in male Wistar rats by tibiotarsal injection of complete Freund’s adjuvant. Mechanical hyperalgesia and DNIC were assessed weekly by the Randall-Selitto test. Immunohistochemistry was used to quantify spinal 5-HT3R, and tryptophan hydroxylase (TPH) colocalization with phosphorylated extracellular signal-regulated protein kinases 1/2 at the rostroventromedial medulla (RVM). Spinal serotonin (5-HT) was quantified by HPLC. The effects of intrathecal ondansetron, a 5-HT3R antagonist, were assessed on mechanical hyperalgesia and DNIC.MA resulted in a prolonged steady-state mechanical hyperalgesia. In contrast, DNIC peaked after 28 days, decreasing afterwards until extinction at 42 days. At this later timepoint, MA rats showed increased: (i) spinal 5-HT3R and 5-HT levels, (ii) neuronal serotonergic activation and TPH expression at the RVM. Ondansetron reversed mechanical hyperalgesia and restored DNIC, regardless of being administered before or after CS. However, data variability was higher upon administration before CS in MA-animals.Prolonged MA upregulates the descending serotonergic modulation, which simultaneously results in increased nociception and DNIC extinction, through 5-HT3R. Our data suggest a role for spinal 5-HT3R in the top-down modulation of DNIC. Additionally, these receptors may also be involved in the bottom-up circuitry implicated in the trigger of DNIC.

Objective evidence for chronic back pain relief by Medical Yoga therapy.

Chronic low back pain (CLBP) is a musculoskeletal ailment that affects millions globally. The pain is disturbing associated with impaired motor activity, reduced flexibility, decreased productivity and strained interpersonal relationships leading to poor quality of life. Inflammatory mediators in vicinity of nociceptors and amplification of neural signals cause peripheral and central sensitization presented as hyperalgesia and/or allodynia. It could be attributed to either diminished descending pain inhibition or exaggerated ascending pain facilitation. Objective measurement of pain is crucial for diagnosis and management. Nociceptive flexion reflex is a reliable and objective tool for measurement of a subject's pain experience. Medical Yoga Therapy (MYT) has proven to relieve chronic pain, but objective evidence-based assessment of its effects is still lacking. We objectively assessed effect of MYT on pain and quality of life in CLBP patients. We recorded VAS (Visual analogue scale), McGill Pain questionnaire and WHOQOL BREF questionnaire scores, NFR response and Diffuse noxious inhibitory control tests. Medical yoga therapy consisted of an 8-week program (4 weeks supervised and 4 weeks at home practice). CLBP patients (42.5 ± 12.6 years) were randomly allocated to MYT (n = 58) and SCT groups (n = 50), and comparisons between the groups and within the groups were done at baseline and at end of 4 and 8 weeks of both interventions. (VAS) scores for patients in both the groups were comparable at baseline, subjective pain rating decreased significantly more after MYT compared to SCT (p = < 0.0001*, p = 0.005*). McGill Pain questionnaire scores revealed significant reduction in pain experience in MYT group compared to SCT. Nociceptive Flexion Reflex threshold increased significantly in MYT group at end of 4 weeks and 8 weeks, p < 0.0001#, p = < 0.0001∞ respectively) whereas for SCT we did not find any significant change in NFR thresholds. DNIC assessed by CPT also showed significant improvement in descending pain modulation after MYT compared to SCT both at end of 4 and 8 weeks. Quality of life also improved significantly more after MYT. Thus, we conclude with objective evidence that Medical Yoga Therapy relieves chronic low back pain, stress and improves quality of life better than standard care.

Characterization of the Dahl salt-sensitive rat as a rodent model of inherited, widespread, persistent pain

Animal models are essential for studying the pathophysiology of chronic pain disorders and as screening tools for new therapies. However, most models available do not reproduce key characteristics of clinical persistent pain. This has limited their ability to accurately predict which new medicines will be clinically effective. Here, we characterize the Dahl salt-sensitive (SS) rat strain as the first rodent model of inherited widespread hyperalgesia. We show that this strain exhibits physiological phenotypes known to contribute to chronic pain, such as neuroinflammation, defective endogenous pain modulation, dysfunctional hypothalamic–pituitary–adrenal axis, increased oxidative stress and immune cell activation. When compared with Sprague Dawley and Brown Norway rats, SS rats have lower nociceptive thresholds due to increased inflammatory mediator concentrations, lower corticosterone levels, and high oxidative stress. Treatment with dexamethasone, the reactive oxygen species scavenger tempol, or the glial inhibitor minocycline attenuated the pain sensitivity in SS rats without affecting the other strains while indomethacin and gabapentin provided less robust pain relief. Moreover, SS rats presented impaired diffuse noxious inhibitory controls and an exacerbated response to the proalgesic mediator PGE2, features of generalized pain conditions. These data establish this strain as a novel model of spontaneous, widespread hyperalgesia that can be used to identify biomarkers for chronic pain diagnosis and treatment.

Monoaminergic mediation of hyperalgesic and analgesic descending control of nociception in mice.

Descending control of nociception (DCN; also known as conditioned pain modulation [CPM], the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pain modulation on the application of a DCN paradigm involving low-intensity test stimuli occurs in the direction of hyperalgesia in healthy mice and rats, whereas the use of high-intensity stimuli produces analgesia. To elucidate the physiological mechanisms underlying hyperalgesic DCN, we administered agonists and antagonists of norepinephrine (NE) and serotonin (5-HT) receptors, key neurochemical players in the production of analgesic DCN. We find that 3 different monoamine reuptake inhibitors-the NE-selective reboxetine, the 5-HT-selective fluoxetine, and the dual NE/5-HT agonist duloxetine-all abolish hyperalgesic DCN when administered into the spinal cord (but not systemically), with no effect on heat or mechanical pain sensitivity. The reversal by reboxetine of hyperalgesic DCN is mediated by α 2 -adrenergic receptors (ie, blocked by atipamezole), and the fluoxetine reversal is mediated by 5-HT 7 receptors (ie, blocked by SB269970). By contrast, analgesic DCN was found to be reversed by atipamezole and SB269970 themselves, with no effect of reboxetine or fluoxetine. Thus, hyperalgesic DCN seems to be the neurochemical opposite to analgesic DCN. These data further validate and help elucidate a preclinical paradigm that mimics dysfunctional CPM and thus may form the basis of translational experiments that aim to reveal preventative pharmacological strategies for individuals predisposed to persistent pain.

Monoamine control of descending pain modulation after mild traumatic brain injury

Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately, the mechanisms underlying pain after TBI are poorly understood. Here we examined the contribution of spinal monoamine signaling to dysfunctional descending pain modulation after TBI. For these studies we used a well-characterized concussive model of mild TBI. Measurements included mechanical allodynia, the efficacy of diffuse noxious inhibitory control (DNIC) endogenous pain control pathways and lumber norepinephrine and serotonin levels. We observed that DNIC is strongly reduced in both male and female mice after mild TBI for at least 12 weeks. In naïve mice, DNIC was mediated through α2 adrenoceptors, but sensitivity to α2 adrenoceptor agonists was reduced after TBI, and reboxetine failed to restore DNIC in these mice. The intrathecal injection of ondansetron showed that loss of DNIC was not due to excess serotonergic signaling through 5-HT3 receptors. On the other hand, the serotonin-norepinephrine reuptake inhibitor, duloxetine and the serotonin selective reuptake inhibitor escitalopram both effectively restored DNIC after TBI in both male and female mice. Therefore, enhancing serotonergic signaling as opposed to noradrenergic signaling alone may be an effective pain treatment strategy after TBI.

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats.

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.

Distinct brainstem to spinal cord noradrenergic pathways inversely regulate spinal neuronal activity.

Brainstem to spinal cord noradrenergic pathways include a locus coeruleus origin projection and diffuse noxious inhibitory controls. While both pathways are traditionally viewed as exerting an inhibitory effect on spinal neuronal activity, the locus coeruleus was previously shown to have a facilitatory influence on thermal nocioception according to the subpopulation of coerulean neurons activated. Coupled with knowledge of its functional modular organisation and the fact that diffuse noxious inhibitory controls are not expressed in varied animal models of chronicity, we hypothesized a regulatory role for the locus coeruleus on non-coerulean, discrete noradrenergic cell group(s).We implemented locus coeruleus targeting strategies by microinjecting canine adenovirus encoding for channelrhodopsin-2 under a noradrenaline-specific promoter in the spinal cord (retrogradely labelling a coeruleospinal module) or the locus coeruleus itself (labelling the entire coerulean module). Coeruleospinal module optoactivation abolished diffuse noxious inhibitory controls (two-way ANOVA, P < 0.0001), which were still expressed following locus coeruleus neuronal ablation.We propose that the cerulean system interacts with, but does not directly govern, diffuse noxious inhibitory controls. This mechanism may underlie the role of the locus coeruleus as a ‘chronic pain generator’. Pinpointing the functionality of discrete top-down pathways is crucial for understanding sensorimotor modulation in health and disease.

The Added Value of Intraoperative Hypnosis during Spinal Cord Stimulation Lead Implantation under Awake Anesthesia in Patients Presenting with Refractory Chronic Pain

To improve pain relief for refractory pain condition, spinal cord stimulation (SCS) needs to target the dedicated neuronal fibers within the dorsal columns. Intraoperative feedback from the patient can optimize lead placement but requires “awake surgery”, allowing interaction between patient and surgeon. This can produce negative effects like anxiety and stress. To better manage these aspects, we propose to combine intraoperative hypnosis with awake anesthesia. Seventy-four patients (35 females, 22–80 years) presenting with chronic refractory pain, were offered intraoperative hypnosis during awake SCS lead implantation. Interactive conversational hypnosis was used as well as interactive touch, which was enhanced during painful moments during the lead intraoperative programming. All patients participated actively during the intraoperative testing which helped to optimize the lead positioning. They kept an extremely positive memory of the surgery and of the hypnotic experience, despite some painful moments. Pain could be reduced in these patients by using interactions and touch, which works on Gate Control modulation. Positive memory was reinforced by congratulations to create self-confidence and to induce positive expectations, which could reinforce the Diffuse Noxious Inhibitory Controls at the spinal level. Cooperation was improved because the patient was actively participating and thus, much more alert when feedback was required. Combining intraoperative hypnosis with awake anesthesia appears helpful for SCS lead implantation. It enhances patient cooperation, allows optimization of lead positioning, and leads to better pain control, positive and resourceful memory.

Effects of Acute and Chronic Stretching on Pain Control

ABSTRACT While muscle stretching has been commonly used to alleviate pain, reports of its effectiveness are conflicting. The objective of this review is to investigate the acute and chronic effects of stretching on pain, including delayed onset muscle soreness. The few studies implementing acute stretching protocols have reported small to large magnitude decreases in quadriceps and anterior knee pain as well as reductions in headache pain. Chronic stretching programs have demonstrated more consistent reductions in pain from a wide variety of joints and muscles, which has been ascribed to an increased sensory (pain) tolerance. Other mechanisms underlying acute and chronic pain reduction have been proposed to be related to gate control theory, diffuse noxious inhibitory control, myofascial meridians, and reflex-induced increases in parasympathetic nervous activity. By contrast, the acute effects of stretching on delayed onset muscle soreness are conflicting. Reports of stretch-induced reductions in delayed onset muscle soreness may be attributed to increased pain tolerance or alterations in the muscle's parallel elastic component or extracellular matrix properties providing protection against tissue damage. Further research evaluating the effect of various stretching protocols on different pain modalities is needed to clarify conflicts within the literature.