Supraspinal Level Research Articles

Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study

Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test – hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. PerspectiveThis exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.

Pramipexole and tolcapone alleviate thermal and mechanical nociception in naive rats.

Parkinson's disease (PD) is а neurodegenerative disorder characterized mainly by its motor symptoms. The non-motor symptoms including pain are increasingly recognized in the last few decades. Existing evidence suggests that the dopaminergic neurotransmission has an essential role in pain control. The aim of the present study was to investigate the antinociceptive effect of dopaminergic drugs pramipexole and tolcapone against chemical and thermal stimuli in naive rats. Male Wistar rats divided into 8 groups (n=8): saline; diclofenac 25 mg/kg body weight (bw) (positive control); pramipexole 0.5; 1 and 3 mg/kg bw; tolacapone 5; 15 and 30 mg/kg bw. Paw pressure and plantar tests were performed. Paw withdrawal pressure and latent time were measured. Statistical analysis was done by SPSS 19. In the paw pressure test, pramipexole, in a dose of 1 and 3 mg/kg bw and tolcapone in a dose of 30 mg/kg bw, increased significantly the latency at 1, 2, and 3 hours compared to saline (p<0.05). In the plantar test, only the highest dose of pramipexole reached significance at 3 hours compared to the control rats (p<0.05). In contrast to pramipexole the three experimental groups with tolcapone markedly increased the latent time at 1 and 3 hours compared to saline (p<0.05). Pramipexole and tolcapone reduce mechanical and thermal nociception in naïve rats by enhancing dopaminergic neurotransmission at both spinal and supraspinal levels. In addition, tolcapone stimulates noradrenergic mediation which may contribute to its antinociceptive effect.

Sex Differences in a Rat Model of Peripheral Neuropathic Pain and Associated Levels of Endogenous Cannabinoid Ligands

Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.

How do Spinal Stabilization Exercises Relieve Back Pain? An Analysis of Potential Mechanisms of Analgesia Effected at Muscular, Spinal Cord and Supraspinal Levels

STUDY OBJECTIVE Spinal stabilization exercises have emerged as an effective treatment for low back pain (LBP), but the mechanism of analgesia obtained through these exercises is unknown. The objective of the present research was to derive viable hypotheses for this pain relief based on previously validated analgesic mechanisms. METHODS A literature review was conducted by first considering commonly known methods of both exogenous and endogenous pain control, and then selecting for deeper analysis those mechanisms which could conceivably be operative during the self-generated, low amplitude movements involved in spinal stabilization exercises. The three chosen analgesic processes were related to perfusion, gate control, and endogenous analgesia. RESULTS Mechanism 1: Increased Perfusion Muscle contraction is known to increase perfusion of muscle tissue, leading to increased nutrient delivery and removal of waste products, and ischemia caused by atherosclerosis causes pain in multiple tissues including muscle. The lumbar blood supply derives from the abdominal aorta/lumbar artery system and blockages in this system have been linked to LBP. Gentle stabilization exercises targeting the core which activate these muscles may thus increase perfusion and thereby lessen pain related to ischemia. Mechanism 2: Gate Control-Mediated Analgesia Since Melzack and Wall first proposed the Gate Control Theory, the existence of multiple specific pain-inhibiting circuits linking dorsal horn laminae has been confirmed. Recent studies support a role for muscle spindles and golgi tendon organs in “closing the gate” to pain sensations, via muscle contraction. Pain relief during contract-relax and resistance exercises has been achieved in at least 3 studies, possibly through activation of these receptors. This process may explain in part the achievement of pain relief obtained after a short course of spinal stabilization exercises. Mechanism 3: Exercise-Induced Analgesia Exercise Induced analgesia (EIA) works through multiple endogenous systems that decrease pain perception, including the opioidergic, serotonergic, noradrenergic, endocannabinoid, and nitrergic systems. Numerous studies have shown EIA occurs with aerobic exercise in both humans and animals. The role of EIA in analgesia during isometric and core stabilization exercises is starting to be explored, including findings that both plasma β-endorphin and serotonin levels increase after core exercises. CONCLUSIONS The manner in which spinal stabilization exercises achieve analgesia is unknown. The vascular, gate-control, and exercise-mediated mechanisms outlined above are known to elicit an analgesic effect, and could conceivably be evoked by the gentle, low amplitude movements of these exercises. Rigorous, prospective research on perfusion of the muscles involved in core stabilization, the activation of muscle proprioceptive pathways in dorsal horn pain synapses, and plasma levels of key hormones during and after core stabilization exercises, would help support or refute the existence of this link.

5‐HT1A Receptor Activation by Buspirone Facilitates Post‐Inflammatory Intestinal Hypersensitivity in a Rat Model

Intestinal hypersensitivity is the most common symptom and cause of pain in patients with post-inflammatory irritable bowel syndrome (PI-IBS). Several lines of evidence suggest that central serotonin (5-HT) and its receptors significantly contribute to the phenomenon and therefore may be prospective therapeutic targets for relieving abdominal pain and discomfort in PI-IBS. We demonstrated previously that buspirone, a partial agonist of the 5-HT1A receptors, dose-dependently inhibited visceromotor reactions and medullary neuronal responses to noxious colorectal distension in healthy awake dogs and anesthetized rats, indicating the drug's antinociceptive properties in normal conditions. However, whether the 5-HT1A agonist can be beneficial for post-inflammatory intestinal hypersensitivity and hyperalgesia, which are thought to be associated with altered central 5-HT signaling, is still unknown. In the presented study, the effect of systemic buspirone (Sigma-Aldrich, USA) on intestinal hypersensitivity and its underlying neuronal mechanisms were evaluated in Wistar rats recovered from trinitrobenzene sulfonic acid (TNBS)-induced colitis. To assess gut sensitivity, the electromyography recordings of visceromotor reaction to colorectal distension (CRD) and extracellular microelectrode recordings of CRD-evoked caudal medulla neuronal responses were performed in conscious and urethane-anesthetized animals respectively. The results showed that in intestinal hypersensitive rats the visceromotor reaction and medullary neuronal responses to CRD in 40-60 days after TNBS treatment, despite the absence of obvious gut damage by this time, were increased compared with those in norm. Subcutaneous injection of buspirone (2 mg/kg), which exerted antinociceptive effect in healthy control group, further enhanced visceromotor reaction to CRD in post-colitis animals. In neurophysiological experiments on intestinal hypersensitivity rats, activation of the 5-HT1A receptors by intravenously administered buspirone (2 and 4 mg/kg) resulted in a dose-dependent increase of the CRD-evoked activity in the majority of the caudal medullary neurons, suggesting that the pro-algesic effect of the drug can at least partially be mediated by its excitatory action at the supraspinal level. These data demonstrate that the 5-HT1A agonist buspirone loses its antinociceptive properties in post-colitis conditions and thus may not be useful for reliving visceral hypersensitivity and hyperalgesia in PI-IBS.

GPR55 in the brain and chronic neuropathic pain

There is a clear need for novel and improved therapeutic strategies for alleviating chronic neuropathic pain, as well as a need for better understanding of brain mechanisms of neuropathic pain, which are less understood than spinal and peripheral mechanisms. The G protein-coupled receptor 55 (GPR55), is a lysophosphatidylinositol (LPI)-sensitive receptor that has also been involved in cannabinoid signaling. It is expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain control system. Behaviors, pharmacology, biochemistry tools, and stereotaxic microinjections were used to determine if GPR55 plays a role in pain control in a chronic constriction injury (CCI) neuropathic pain model in rats. It was found that the blockade of GPR55 action in the PAG can restore and drive a descending control system to mitigate neuropathic pain.Our data demonstrate that GPR55 play a role in the descending pain control system, and identify GPR55 at supraspinal level as a neuropathic pain brain mechanism.

The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice

Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER). It is able to decrease the size of xenografted human breast tumors, in mice. As GPER has been reported to participate in pain and inflammation, we were interested in exploring the potential of ERα17p in this respect. We observed that the peptide promoted anti-hyperalgesic effects from 2.5 mg/kg in a chronic mice model of paw inflammation induced by the pro-inflammatory complete Freund’s adjuvant (CFA). This action was abrogated by the specific GPER antagonist G-15, leading to the conclusion that a GPER-dependent mechanism was involved. A systemic administration of a Cy5-labeled version of the peptide allowed its detection in both, the spinal cord and brain. However, ERα17p-induced anti-hyperalgesia was detected at the supraspinal level, exclusively. In the second part of the study, we have assessed the anti-inflammatory action of ERα17p in mice using a carrageenan-evoked hind-paw inflammation model. A systemic administration of ERα17p at a dose of 2.5 mg/kg was responsible for reduced paw swelling. Overall, our work strongly suggests that GPER inverse agonists, including ERα17p, could be used to control hyperalgesia and inflammation.

Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain.

Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. A partial sciatic nerve ligation was performed to wild-type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO-HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain-resistant phenotype of Fmr1KO mice. Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain-induced depressive-like behaviour was observed in WT, HzCB2 and Fmr1KO-HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra-spinal levels that correlated with these nociceptive and emotional alterations. This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain-resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools.

Adrenergic modulation of dexketoprofen antinociception in murine formalin orofacial pain

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in pain whose mechanism of action is the inhibition of cyclooxygenase enzymes (COXs), however, there are evidence of other mechanisms of action, such as the inhibition of substance P, interaction with systems NO, monoaminergic and others. The objective of the present work was to study the participation of a-1 (prazosin) and a-2 (yohimbine) adrenoceptors antagonists in the antinociception of dexketoprofen, the S (+) enantiomer of ketoprofen. The antinociception evaluation was thru the mice orofacial formalin assay. Dexketoprofen (DEX) induced a dose-related antinociception 3.40 times more potent in phase I than in phase II. Prazosin i.p. decreased of the antinociception of DEX, 2.01 times in phase I and 4.02 times in phase II. Administered i.t. reduced the antinociception 5.30 times in phase I and 6.20 times in phase II. Yohimbine i.p. induced a reduction of the ED50 of 3.40 times in phase I and 4.50 times in phase II, after i.t. administration the reduction was 5.30 times in phase I and 6.20 times in phase II. The mechanism of antinociception induced by DEX is mediated by the activation of α-1 and α-2 adrenergic receptors at supraspinal and spinal levels.

Cutaneous and muscular afferents from the foot and sensory fusion processing: Physiology and pathology in neuropathies.

The foot-sole cutaneous receptors (section 2), their function in stance control (sway minimisation, exploratory role) (2.1), and the modulation of their effects by gait pattern and intended behaviour (2.2) are reviewed. Experimental manipulations (anaesthesia, temperature) (2.3 and 2.4) have shown that information from foot sole has widespread influence on balance. Foot-sole stimulation (2.5) appears to be a promising approach for rehabilitation. Proprioceptive information (3) has a pre-eminent role in balance and gait. Reflex responses to balance perturbations are produced by both leg and foot muscle stretch (3.1) and show complex interactions with skin input at both spinal and supra-spinal levels (3.2), where sensory feedback is modulated by posture, locomotion and vision. Other muscles, notably of neck and trunk, contribute to kinaesthesia and sense of orientation in space (3.3). The effects of age-related decline of afferent input are variable under different foot-contact and visual conditions (3.4). Muscle force diminishes with age and sarcopenia, affecting intrinsic foot muscles relaying relevant feedback (3.5). In neuropathy (4), reduction in cutaneous sensation accompanies the diminished density of viable receptors (4.1). Loss of foot-sole input goes along with large-fibre dysfunction in intrinsic foot muscles. Diabetic patients have an elevated risk of falling, and vision and vestibular compensation strategies may be inadequate (4.2). From Charcot-Marie-Tooth 1A disease (4.3) we have become aware of the role of spindle group II fibres and of the anatomical feet conditions in balance control. Lastly (5) we touch on the effects of nerve stimulation onto cortical and spinal excitability, which may participate in plasticity processes, and on exercise interventions to reduce the impact of neuropathy.

Insights into the combination of neuromuscular electrical stimulation and motor imagery in a training-based approach

IntroductionTraining stimuli that partially activate the neuromuscular system, such as motor imagery (MI) or neuromuscular electrical stimulation (NMES), have been previously shown as efficient tools to induce strength gains. Here the efficacy of MI, NMES or NMES + MI trainings has been compared.MethodsThirty-seven participants were enrolled in a training program of ten sessions in 2 weeks targeting plantar flexor muscles, distributed in four groups: MI, NMES, NMES + MI and control. Each group underwent forty contractions in each session, NMES + MI group doing 20 contractions of each modality. Before and after, the neuromuscular function was tested through the recording of maximal voluntary contraction (MVC), but also electrophysiological and mechanical responses associated with electrical nerve stimulation. Muscle architecture was assessed by ultrasonography.ResultsMVC increased by 11.3 ± 3.5% in NMES group, by 13.8 ± 5.6% in MI, while unchanged for NMES + MI and control. During MVC, a significant increase in V-wave without associated changes in superimposed H-reflex has been observed for NMES and MI, suggesting that neural adaptations occurred at supraspinal level. Rest spinal excitability was increased in the MI group while decreased in the NMES group. No change in muscle architecture (pennation angle, fascicle length) has been found in any group but muscular peak twitch and soleus maximal M-wave increased in the NMES group only.ConclusionFinally, MI and NMES seem to be efficient stimuli to improve strength, although both exhibited different and specific neural plasticity. On its side, NMES + MI combination did not provide the expected gains, suggesting that their effects are not simply cumulative, or even are competitive.

Сенсибилизация гепарином мю-рецепторов, инициированных фентанилом

Heparin is an anticoagulant widely used in clinical practice. In addition to anticoagulant activity, heparin has a cytostatic, bacteriostatic, antilipemic, radioprotective effect, and exhibits antiallergic and hypotensive action. Heparin modulates cardiotropic, neurotropic, antihypoxic, anti-ischemic properties of regulatory peptides and pharmacological agents used in pain relief and anesthesia. At the same time, there is very little information about the antinociceptive effect of heparin. The aim of this work is to study the effect of heparin in combination with the opioid agonist fentanyl on mu-opioid receptors at the spinal and supraspinal levels. In experiments on laboratory rats, it was established that heparin, when pre-administered and combined with fentanyl, increases the latency in the tail flick test and the paw licking test. Naloxone, an opioid receptor antagonist, reduces antinociceptive efficacy of the studied compounds. Protamine sulfate also reduces the level of heparin sensitization of opioid receptors. Thus, the obtained data allow us to speak about the sensitizing effect of heparin on initiated by an agonist mu-opioid receptors at the spinal and supraspinal levels.

Systematic Review of the Use of Intravenous Ketamine for Fibromyalgia.

Background: Fibromyalgia, a complex disorder that affects 1% to 5% of the population, presents as widespread chronic musculoskeletal pain without physical or laboratory signs of any specific pathologic process. The mechanism, while still being explored, suggests central sensitization and disordered pain regulation at the spinal cord and supraspinal levels, with a resulting imbalance between excitation and inhibition that may alter central nervous system nociceptive processing. Nociceptive hypersensitivity results from activity of the N-methyl-D-aspartate receptor (NMDAR)–mediated glutamatergic synaptic transmission in the spinal cord and brain. Because ketamine, an NMDAR antagonist, may reduce induction of synaptic plasticity and maintenance of chronic pain states, the study of its use in intravenous form to treat fibromyalgia has increased.Methods: We conducted a literature search with the objectives of examining the effect of intravenous ketamine administration on pain relief, identifying side effects, and highlighting the need for clinical studies to evaluate ketamine infusion treatment protocols for patients with fibromyalgia. We used the keywords “fibromyalgia,” “chronic pain,” “ketamine,” “intravenous,” and “infusion” and found 7 publications that included 118 patients with fibromyalgia who met inclusion criteria.Results: Clinical studies revealed a short-term reduction—only for a few hours after the infusions—in self-reported pain intensity with single, low-dose, intravenous ketamine infusions, likely attributable to nociception-dependent central sensitization in fibromyalgia via NMDAR blockade. Case studies suggest that increases in the total dose of ketamine and longer, more frequent infusions may be associated with more effective pain relief and longer-lasting analgesia. Another neurotransmitter release may be contributing to this outcome.Conclusion: This systematic review suggests a dose response, indicating potential efficacy of intravenous ketamine in the treatment of fibromyalgia.

Organ cross-sensitization mechanisms in chronic diseases related to the genitourinary tract.

There are various refractory chronic inflammatory diseases related to the genitourinary tract, such as interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. It has been reported that in the general population, these diseases are related to other chronic illnesses, such as irritable bowel syndrome or vulvodynia. Herein, we review papers regarding pelvic organ cross-sensitization, a factor which is considered to contribute to these relationships. Several other researchers and ourselves have reported that noxious stimuli from a diseased pelvic organ are transmitted to an adjacent normal structure via shared sensory neural pathways at the prespinal, spinal, and supraspinal levels, resulting in functional changes in the adjacent normal structure. In conclusion, since there are few treatments to cure interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome completely, further studies regarding organ cross-sensitization may provide new insights into the pathophysiology and treatment strategies for these diseases.

Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review.

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named “non-neuronal cells.” In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells—and therefore the control of neuroinflammation—depends on the local “on demand” synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide—either by decreasing its degradation or exogenous administration—is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

BackgroundHuman immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.MethodsHere, we examined the impact of chronic (3-month) HIV-1 transactivator of transcription (Tat) exposure to short-term (8-day), escalating morphine in HIV-1 Tat transgenic mice that express the HIV-1 Tat protein in a GFAP promoter-regulated, doxycycline (DOX)-inducible manner. In addition to assessing morphine-induced tolerance in nociceptive responses organized at spinal (i.e., tail-flick) and supraspinal (i.e., hot-plate) levels, we evaluated neuroinflammation via positron emission tomography (PET) imaging using the [18F]-PBR111 ligand, immunohistochemistry, and cytokine analyses. Further, we examined endocannabinoid (eCB) levels, related non-eCB lipids, and amino acids via mass spectrometry. ResultsTat-expressing [Tat(+)] transgenic mice displayed antinociceptive tolerance in the tail withdrawal and hot-plate assays compared to control mice lacking Tat [Tat(−)]. This tolerance was accompanied by morphine-dependent increases in Iba-1 ± 3-nitrotryosine immunoreactive microglia, and alterations in pro- and anti-inflammatory cytokines, and chemokines in the spinal cord and striatum, while increases in neuroinflammation were absent by PET imaging of [18F]-PBR111 uptake. Tat and morphine exposure differentially affected eCB levels, non-eCB lipids, and specific amino acids in a region-dependent manner. In the striatum, non-eCB lipids were significantly increased by short-term, escalating morphine exposure, including peroxisome proliferator activator receptor alpha (PPAR-α) ligands N-oleoyl ethanolamide (OEA) and N-palmitoyl ethanolamide (PEA), as well as the amino acids phenylalanine and proline. In the spinal cord, Tat exposure increased amino acids leucine and valine, while morphine decreased levels of tyrosine and valine but did not affect eCBs or non-eCB lipids.ConclusionOverall results demonstrate that 3 months of Tat exposure increased morphine tolerance and potentially innate immune tolerance evidenced by reductions in specific cytokines (e.g., IL-1α, IL-12p40) and microglial reactivity. In contrast, short-term, escalating morphine exposure acted as a secondary stressor revealing an allostatic shift in CNS baseline inflammatory responsiveness from sustained Tat exposure.

Motor learning adaptations at the spinal cord level are task- and time-dependent: Implications for future investigations and treatment interventions.

Motor learning adaptations at the spinal cord level are task- and time-dependent: Implications for future investigations and treatment interventions.

The Effect of Low-Level Light Therapy on Capsaicin-Induced Peripheral and Central Sensitization in Healthy Volunteers: A Double-Blinded, Randomized, Sham-Controlled Trial.

IntroductionSeveral clinical trials have demonstrated that low-level light therapy (LLLT), a method of photobiomodulation, is an effective analgetic treatment. However, the mechanism of action has not yet been finally clarified. In particular, unanswered questions include whether it only affects peripheral or whether it also affects the spinal or supraspinal level. This study aimed to evaluate the effect of low-level light therapy on primary and secondary hyperalgesia in a human pain model.MethodsThis study was planned as a randomized, sham-controlled, and double-blinded trial with repeated measures within subject design. Capsaicin was applied on both forearms of ten healthy volunteers to induce peripheral and central sensitization. One forearm was treated with low-level light therapy; the other served as sham control.ResultsLow-level light therapy significantly increased the mechanical pain threshold, heat pain threshold, and decreased pain intensity.ConclusionsOur data indicate that low-level light therapy is effective at reducing the heat and mechanical pain threshold in a human pain model, pointing to a significant modulating effect on peripheral and central sensitization. These effects—especially in the absence of reported side effects—make low-level light therapy a promising tool in pain management. The application of low-level light therapy to treat chronic pain should be considered for further clinical trials.

Combination of Stressors in the Critical Periods of Development Increases Resistance to Inflammatory Pain Stress in Adult Rats

We report here studies of the long-term effects of combined stress in the prenatal and prepubertal periods of development on measures of tonic inflammatory pain in the formalin test and the severity of depression-like behavior, and also the stress reactivity of the hormonal response in adult rats. In addition, the effects of the serotonin (5-HT) reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone, given chronically to stressed mothers during pregnancy, on various types of adaptive behavior impaired by prenatal stress were assessed in rats of both sexes. The results showed that in rats of both sexes prenatal stress increased the pain response organized at the spinal and supraspinal levels of the central nervous system and that fluoxetine and buspirone normalized responses. Stress during the prepuberal period of development eliminated the effects of prenatal stress on the inflammatory pain responses integrated at the supraspinal level in adult rats; in these conditions, fluoxetine and buspirone had no effects, in contrast to their antinociceptive actions on the pain response integrated at the spinal level. Stress at prepubertal age eliminated sex-related differences seen in depression-like behavior in prenatally unstressed and prenatally stressed rats given physiological saline. Control adult females and adult females exposed to prenatal stress in the prepubertal period showed increases in the plasma corticosterone level after forced swimming as compared with the basal hormone level, though there were no significant differences in the level of stress reactivity of the hormonal response after forced swimming. Thus, the conditions for stress actions increasing stress resistance in adult rats were identified. Stress in the critical period of development formed a phenotype with increased stress resistance to inflammatory pain, which was seen in responses organized at the supraspinal level in adult individuals.

The indirect γ-aminobutyric acid (GABA) receptor agonist gabaculine-induced loss of the righting reflex may inhibit the descending analgesic pathway

In the spinal cord, γ-aminobutyric acid (GABA) interneurons play an essential role in antinociception. However, not all actions of GABA favor antinociception at the supraspinal level. We previously reported that gabaculine, which increases endogenous GABA in the synaptic clefts, induces loss of the righting reflex (LORR) that is one indicator of hypnosis, but not immobility in response to noxious stimulus. A slow pain is transmitted to the spinal cord via C fibers and evokes substance P (SP) release from their terminals. However, the antinociceptive effects of gabaculine are still unknown. Our study examined whether the analgesic effects of the opioid morphine or the α2-adrenoceptor agonist dexmedetomidine, whose actions are mediated through facilitation of the descending analgesic pathway, are affected by gabaculine-induced LORR. We also explored the effects of GABA receptor agonists on SP release from cultured dorsal root ganglion (DRG) neurons. All drugs were administered systemically to mice. To assess antinociception, loss of nociceptive response (analgesia) and immobility were evaluated. DRG cells were dissected from rats. Gabaculine produced no analgesia. Either morphine or dexmedetomidine in combination with gabaculine induced immobility; however, the doses of each drug required to induce immobility were much higher than those required to induce analgesia. Capsaicin significantly increased SP release from DRG cells, but a high concentration (1 mM) of the GABA receptor agonist muscimol, propofol, gaboxadol, or baclofen did not inhibit the capsaicin-induced SP release, suggesting that their antinociceptive effects were not through this mechanism. Thus, the gabaculine-induced LORR may inhibit the descending analgesic pathway.