Antinociceptive Processes Research Articles

Physical activity, sitting time, and thermal quantitative sensory testing responses in African Americans.

Prior research suggests that African Americans (AAs) have more frequent, intense, and debilitating pain and functional disability compared with non-Hispanic Whites (NHWs). Potential contributing factors to this disparity are physical activity and sedentary behavior, given that AAs are less physically active, and physical activity is associated with antinociception (whereas sedentary behavior is linked to pronociception). However, impact of these factors on pain processing has largely been unexplored in AAs, especially before chronic pain onset. This study examined relationships between physical activity, sedentary behavior (sitting time), and laboratory measures of pain and pain modulation in adult AAs. These included heat pain threshold and tolerance, temporal summation of pain (TSP, a marker of central sensitization), and conditioned pain modulation (CPM, a marker of descending pain inhibition). Multiple regressions were conducted to examine the effects of physical activity and sitting time on heat threshold and tolerance. Multilevel models were conducted to assess the relationship between physical activity, sitting time, and temporal summation of pain. Additional multilevel models were conducted to assess the relationship between physical activity, sitting time, and conditioned pain modulation. Higher level of physical activity, but not sitting time, was associated with reduced TSP slopes. Neither physical activity nor sitting time was associated with CPM slopes. No significant relationships between physical activity or sitting time and heat pain threshold or tolerance were detected. These findings suggest that physical activity is associated with reduced TSP, an effect which may be driven by reduced spinal hyperexcitability in more active individuals. Thus, structural and individual interventions designed to increase physical activity in healthy, young AAs may be able to promote antinociceptive processes (ie, reduced TSP/reduced pain facilitation) potentially protective against chronic pain.

Investigation of Correlations Between Pain Modulation Paradigms.

Endogenous pain modulation can be quantified through the use of various paradigms. Commonly used paradigms include conditioned pain modulation (CPM), offset analgesia (OA), spatial summation of pain (SSP), and temporal summation of pain (TSP), which reflect spatial and temporal aspects of pro- and antinociceptive processing. Although these paradigms are regularly used and are of high clinical relevance, the underlying physiological mechanisms are not fully understood. The aim of this study is therefore to assess the association between these paradigms by using comparable protocols and methodological approaches. University campus. Healthy and pain-free volunteers (n = 48) underwent psychophysical assessment of CPM, OA, SSP, and TSP (random order) at the same body area (volar nondominant forearm) with individualized noxious stimuli. CPM included heat stimuli before, during, and after a noxious cold-water bath, whereas for OA, three heat stimuli were applied: baseline trial, offset trial, and constant trial. For the SSP paradigm, two differently sized heat stimulation areas were evaluated, whereas for TSP, the first and last stimulus of 10 consecutive short heat stimuli were assessed. A computerized visual analog scale was used to continuously evaluate pain intensity. The magnitudes of all associations between all paradigm pairs were analyzed with Spearman's correlation, and individual influencing factors were assessed with a multivariate linear regression model. Weak to moderate correlations among all four paradigms were found (P > 0.05), and no distinct influencing factors were identified. A limited association between pain modulation paradigms suggests that CPM, OA, SSP, and TSP assess distinct aspects of endogenous analgesia with different underlying physiological mechanisms.

Repeated administration of a flavonoid-based formulated extract from citrus peels significantly reduces peripheral inflammation-induced pain in the rat.

Depression‐related disorders are the first cause of disability worldwide according to the World Health Organization, and there is limited availability of effective antidepressant medications without side effects. Similarly, pain management is a public health concern particularly due to the increase in use of opioid medications, which have a significant side effect profile. Flavonoids can modulate numerous physiological functions including emotional and anti‐nociceptive processes. Gold lotion (GL) is a natural product based on the extract of six citrus peels rich in flavonoids (0.45 mg/ml) with numerous reported biological activities. In the present study, we investigated the effect of repeated administration of GL in a battery of behavioral tests, including the open field test (OFT), forced swim test (FST), and von Frey test (vFT), in rats. While the OFT measured anxiolytic‐related effects, the FST evaluated depression‐related behavior. The vFT evaluated mechanical allodynia in two rat models of peripheral inflammation induced by carrageenan or complete Freund's adjuvant (CFA) administration. Treatment with GL reduced mechanical allodynia after either carrageenan or CFA administration. On the other hand, repeated GL administration did not modulate any behavior evaluated by OFT or FST. Consumption of GL inhibits behavioral signs of inflammatory pain. Therefore, GL may be a valuable analgesic product to be used for inflammatory pain.

Role of hippocampal dopamine receptors in the antinociceptive responses induced by chemical stimulation of the lateral hypothalamus in animal model of acute pain

Dopamine is the predominant catecholamine neurotransmitter in the mammalian brain which has been shown to play a critical role in antinociceptive process. Previous studies have shown that the role of CA1 region of the hippocampus in antinociception induced by stimulation of the lateral hypothalamus (LH) through the dopaminergic system in tonic pain. In this study, we tried to assess the involvement of intra-hippocampal D1- and D2-like dopamine receptors in the LH stimulation-induced antinociception during the tail-flick test as an animal model of acute pain. Ninety-five male Wistar rats were unilaterally implanted with two separate cannulae into the LH and CA1. Animals received intra-CA1 infusion of SCH-23390 (0.25, 1 and 4 µg/rat), as a D1-like dopamine receptor antagonist and sulpiride (0.125, 0.25, 1 and 4 µg/rat), as a D2-like dopamine receptor antagonist, 2 min before intra-LH administration of carbachol (250 nM/rat). The antinociceptive effects of SCH-23390 and sulpiride were measured by using a tail-flick analgesiometer and represented as the maximal possible effect (%MPE). Also, the locomotion tracking apparatus was used to measure the locomotor activity of animals. Results showed that intra-CA1 administration of SCH-23390 or sulpiride could prevent the intra-LH carbachol-induced antinociception. This effect was a little more dominant after blocking the D2-like dopamine receptor in the CA1. These findings revealed that D1- and D2-like dopamine receptors within the CA1 play an important role in antinociceptive responses induced by chemical stimulation of the LH. It could be suggested that dopamine receptors in the CA1 were triggered by LH orexinergic projections.

Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception.

Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0 μg/0.2 μL) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64 mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0 min) and subsequently at 10-min intervals until 130 min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130 min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity.

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. 48h 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.

Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role?

Recently, there has been interest in lysergic acid diethylamide (LSD) and psilocybin for depression, anxiety and fear of death in terminal illness. The aim of this review is to discuss the potential use of LSD and psilocybin for patients with persistent pain. LSD and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. Tentative evidence from a systematic review suggests that LSD (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. LSD and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness.

Antinociceptive and Antibacterial Properties of Anthocyanins and Flavonols from Fruits of Black and Non-Black Mulberries.

Anthocyanins and flavones are important pigments responsible for the coloration of fruits. Mulberry fruit is rich in anthocyanins and flavonols, which have multiple uses in traditional Chinese medicine. The antinociceptive and antibacterial activities of total flavonoids (TF) from black mulberry (MnTF, TF of Morus nigra) and non-black mulberry (MmTF, TF of Morus mongolica; and MazTF, TF of Morus alba ‘Zhenzhubai’) fruits were studied. MnTF was rich in anthocyanins (11.3 mg/g) and flavonols (0.7 mg/g) identified by ultra-performance liquid chromatography–tunable ultraviolet/mass single-quadrupole detection (UPLC–TUV/QDa). Comparatively, MmTF and MazTF had low flavonol contents and MazTF had no anthocyanins. MnTF showed significantly higher antinociceptive and antibacterial activities toward Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus than MmTF and MazTF. MnTF inhibited the expression of interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), phospho-p65 (p-p65) and phospho-IκBα (p-IκBα), and increased interleukin 10 (IL-10). Additionally, mice tests showed that cyanidin-3-O-glucoside (C3G), rutin (Ru) and isoquercetin (IQ) were the main active ingredients in the antinociceptive process. Stronger antinociceptive effect of MnTF was correlated with its high content of anthocyanins and flavonols and its inhibitory effects on proinflammatory cytokines, iNOS and nuclear factor-κB (NF-κB) pathway-related proteins.

Resolving the Brainstem Contributions to Attentional Analgesia.

Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity (p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands.SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.

The contribution of activated peripheral kappa opioid receptors (kORs) in the inflamed knee joint to anti-nociception

The systemic administration of opioids can be used for their strong analgesic effect. However, extensive activation of opioid receptors (ORs) beyond the targeted tissue can cause dysphoria, pruritus, and constipation. Therefore, selective activation of peripheral ORs present in the afferent fibers of the targeted tissue can be considered a superior strategy in opioid analgesia to avoid potential adverse effects. The purpose of this study was to clarify the role of peripheral kappa opioid receptors (kORs) in arthritic pain for the possible use of peripheral ORs as a target in anti-nociceptive therapy.We administered U50488 or nor-BNI/DIPPA, a selective agonist or antagonist of kOR, respectively into arthritic rat knee joints induced using 1% carrageenan. After the injection of U50488 or U50488 with nor-BNI or DIPPA into the inflamed knee joint, we evaluated nociceptive behavior as indicated by reduced weight-bearing on the ipsilateral limbs of the rat and recorded the activity of mechanosensitive afferents (MSA).In the inflamed knee joint, the intra-articular application of 1μM, 10nM, or 0.1nM U50488 resulted in a significant reduction in nociceptive behavior. In addition, 1μM and 10nM U50488 decreased MSA activity. However, in a non-inflamed knee joint, 1μM U50488 had no effect on MSA activity. Additionally, intra-articular pretreatment with 20μM nor-BNI or 10μM DIPPA significantly blocked the inhibitory effects of 1μM U50488 on nociceptive behavior and MSA activity in the inflamed knee joint.These results implicate that peripheral kORs can contribute to anti-nociceptive processing in an inflamed knee joint.

Dorsal raphe nucleus acetylcholine-mediated neurotransmission modulates post-ictal antinociception: The role of muscarinic and nicotinic cholinergic receptors

The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.

Role of corticotropin-releasing hormone receptor 1 in the regulation of nociception in mice

Corticotropin-releasing hormone (CRH) is known to be involved in both antinociceptive and nociceptive processing. In the present study, we examined the role of the CRH receptor 1 in the regulation of nociception in mice. First, we found that CRH mRNA level was elevated in the hypothalamus or hippocampus by intraperitoneal (i.p.) injection with 1% acetic acid, intraplantar injection of 5% formalin, or intrathecal (i.t.) injection of substance P (0.7 μg/5 μl). Nociceptive behavior induced by acetic acid, formalin, or substance P were reduced in CRHR1 heterozygous (CRHR1+/−) mice compared to that in C57BL6 (wild type, CRHR1+/+) mice group. Furthermore, administration with CRHR1 antagonists such as CP 154526 (10 mg/kg, i.p.) or α-helical CRF 9-41 (10 μg/5 μl, intracerebroventricular [i.c.v.]) attenuated nociceptive behaviors observed in the substance P and writhing pain models. Our results suggest that CRHR1 might play an important role in the regulation of nociception, especially, toward nociceptive activation rather than producing the antinociception.

Effects of two different specific neck exercise interventions on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck shoulder pain.

Chronic neck/shoulder pain (CNSP) is one of the most common pain conditions. The understanding of mechanisms, including the peripheral balance between nociceptive and antinociceptive processes, is incomplete. N-acylethanolamines (NAEs) are a class of endogenous compounds that regulate inflammation and pain. The aim of this study was to investigate the levels of two NAEs: the peroxisome proliferator-activated receptor type-α ligand palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) in the muscle interstitium of the trapezius muscle in women with CNSP randomized to two different neck specific training programs and in a healthy pain-free control group (CON). Fifty-seven women with CNSP were randomized to strength + stretch or stretch alone exercise programs. Twenty-nine subjects underwent microdialysis procedure before and after 4-6 months of exercise. Twenty-four CON subjects underwent microdialysis procedure before and after 4-6 months without any intervention in between. Microdialysate samples were collected from the trapezius muscle and analyzed by mass spectrometry for PEA and SEA levels. PEA and SEA levels were significantly higher in CNSP patients compared with CON. PEA was significantly higher in CNSP than in CON after both training programs. SEA was significantly higher in CNSP than in CON after stretch alone but not after strength + stretch training. A significant positive correlation was found between changes in pain intensity and in SEA levels in the strength + stretch group, but not in the stretch alone group. Our results indicate that exercise interventions differentially affect the levels of the bioactive lipids PEA and SEA in the interstitium of the trapezius muscle in women with CNSP.

Intrinsic connections within the pedunculopontine tegmental nucleus are critical to the elaboration of post‐ictal antinociception

This study investigated the intrinsic connections of a key-structure of the endogenous pain inhibitory system, the pedunculopontine tegmental nucleus (PPTN), in post-ictal antinociceptive process through synaptic inactivation of the PPTN with cobalt chloride. Male Wistar rats (n = 6 or 7 per group), weighing 250-280 g, had the tail-flick baseline recorded and were submitted to a stereotaxic surgery for the introduction of a guide-cannula aiming at the PPTN. After 5 days of postoperative recovery, cobalt chloride (1 mM/0.2 µL) or physiological saline (0.2 µL) were microinjected into the PPTN and after 5 min, the tail-withdrawal latency was measured again at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 min after seizures evoked by intraperitoneal injection of pentylenetetrazole (64 mg/kg). The synaptic inactivation of PPTN decreased the post-ictal antinociceptive phenomenon, suggesting the involvement of PPTN intrinsic connections in the modulation of pain, during tonic-clonic seizures. These results showed that the PPTN may be crucially involved in the neural network that organizes the post-ictal analgesia.

Resting state connectivity correlates with drug and placebo response in fibromyalgia patients

Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response.We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition.15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex.This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.

Exploring cerebral networks in cluster headache: Insights and perspectives

In the last several years, neuroimaging studies have greatly increased our knowledge of cluster headache (CH) pathophysiology (1). The main neuroimaging techniques used to investigate functional and structural changes in CH include positron-emission tomography (PET) (2,3), functional magnetic resonance imaging (fMRI) (4–6), structural magnetic resonance imaging (sMRI) (7–9) and diffusion tensor imaging (DTI) (9–11). PET and fMRI indirectly measure the neural activity that assesses, respectively, regional glucose uptake and blood oxygen level-dependent (BOLD) signal during the execution of a task or in resting state condition (12). Advances in fMRI data processing, such as the use of independent component analyses and correlation analyses among signals detected in defined brain regions, have allowed researchers to assess the temporal dependency of neural activation patterns of spatially separated brain regions and therefore to investigate functional connectivity. While fMRI can assess functional connectivity, structural connectivity can be assessed with DTI (13). This imaging technique measures local fractional anisotropy (direction of water molecules diffusion) and enables mapping of white matter tracts. The imaging technique sMRI investigates structural brain abnormalities by assessing macroscopic volumetric changes of gray matter tissue, using methods such as voxel-based morphometry (VBM) (14) and the measure of cortical thickness (15). Seminal PET studies initially suggested that the ipsilateral posterior hypothalamic area played a key role as the cluster headache generator (generator of pain attacks) (2,3). This result was supported by an sMRI study that showed volumetric abnormality of this structure (8). However, long-term results on the efficacy of deep brain stimulation (DBS) in CH (16) indicated that the hypothalamus is not the trigger of CH attacks but might play a role in the dynamic interactions between not-yet known cortical and subcortical areas and the hypothalamo-trigeminal pathway (17). Other brain regions in the so-called pain matrix could play a role in CH pathophysiology (18). Indeed, during CH attacks, a PET study showed the involvement of brain regions related to pain processing, such as the anterior and posterior cingulate cortices and the insular and orbitofrontal cortices (2). More recently, a DTI study has shown microstructural changes in similar brain areas belonging to the pain network (10). Accordingly, resting state fMRI studies reported abnormal functional connectivity between the hypothalamus and pain-related regions during CH attacks (4). Interestingly, diffuse abnormal functional connectivity was also reported in areas beyond the pain matrix network during (4) and outside (5) the attack period. To understand anatomic pathways employed by DBS to improve CH and facilitate a more precise patient-specific targeting of DBS, Clelland and colleagues used probabilistic DTI to map the common connectivity of DBS-targeted regions (19). They showed that DBS targets project to the ipsilateral hypothalamus, the ipsilateral reticular formation, and the ipsilateral cerebellum, therefore indicating that anatomical regions corresponding to successful DBS are connected to some areas involved in antinociceptive processing. The limitations of the study, well discussed by the authors, suggest caution in the interpretation and the generalization of the results to the chronic cluster headache population. This study considered a small number of healthy participants. A lack of statistical power due to small sample size is likely the root cause of some variability in the network target of the DBS. Indeed, some participants also showed projections to

Anti-inflammatory and Antinociceptive Activity of Chitin-binding Lectin from Canna Limbata Seeds

Lectins are a structurally heterogeneous group of proteins or glycoproteins with at least one noncatalytic domain binding reversibly to a specific mono- or oligosaccharide. Monocot mannose-binding lectins are an extended superfamily of structurally and evolutionarily related proteins. In this study, we evaluated anti-inflammatory and antinociceptive effects of monocot lectin from the Canna limbata seeds (CLL). To accomplish this, CLL was purified and subjected to pharmacological assays: abdominal writhing induced by acetic acid, formalin, hot plate and Zymosan A-induced peritonitis tests. The CLL was purified by chromatographic chitin column, and the relative mass of 21 kDa observed in electrophoresis was confirmed by electrospray mass spectrometry, which also revealed that purified CLL consists of a dimer having a weight of 49,676 Da. The CLL showed nociceptive activity in the acetic acid test as well as peripheral antinociceptive response. The CLL also showed anti-inflammatory effect with the reduction of inflammation in the formalin test and neutrophil migration into the peritoneal cavity. This is the first report of anti-inflammatory activity for a monocot lectin, and it suggests a new pharmacological tool to understand inflammatory and antinociceptive processes mediated through lectins.

Neuroanatomical and neuropharmacological approaches to postictal antinociception‐related prosencephalic neurons: the role of muscarinic and nicotinic cholinergic receptors

Several studies have suggested the involvement of the hippocampus in the elaboration of epilepsy. There is evidence that suggests the hippocampus plays an important role in the affective and motivational components of nociceptive perception. However, the exact nature of this involvement remains unclear. Therefore, the aim of this study was to determine the role of muscarinic and nicotinic cholinergic receptors in the dorsal hippocampus (dH) in the organization of postictal analgesia. In a neuroanatomical study, afferent connections were found from the somatosensory cortex, the medial septal area, the lateral septal area, the diagonal band of Broca, and the dentate gyrus to the dH; all these areas have been suggested to modulate convulsive activity. Outputs to the dH were also identified from the linear raphe nucleus, the median raphe nucleus (MdRN), the dorsal raphe nucleus, and the locus coeruleus. All these structures comprise the endogenous pain modulatory system and may be involved either in postictal pronociception or antinociception that is commonly reported by epileptic patients. dH-pretreatment with cobalt chloride (1.0 mmol/L CoCl2/0.2 μL) to transiently inhibit local synapses decreased postictal analgesia 10 min after the end of seizures. Pretreatment of the dH with either atropine or mecamylamine (1.0 μg/0.2 μL) attenuated the postictal antinociception 30 min after seizures, while the higher dose (5.0 μg/0.2 μL) decreased postictal analgesia immediately after the end of seizures. These findings suggest that the dH exerts a critical role in the organization of postictal analgesia and that muscarinic and nicotinic cholinergic receptor-mediated mechanisms in the dH are involved in the elaboration of antinociceptive processes induced by generalized tonic-clonic seizures.

Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”.

Antinociception in piauçu fish induced by exposure to the conspecific alarm substance

Defense and antinociceptive responses can be elicited simultaneously by learned or innate danger signals when an organism is in imminent danger. Antinociception blocks the recuperative behavioral reactions following pain perception that could interfere with defensive efforts. Antinociception associated with fearful experiences involving a confrontation with a predator or a predator being in close proximity is well studied in mammals, but very little is known about how fear affects antinociception responses in fish. Antipredator behavior in Ostariophysan fish may be elicited by exposure to conspecific alarm substance (CAS) that can trigger a fear reaction. During the predator versus prey confrontation, the alarm pheromone system is activated and warns conspecifics about the assessment of predation risk. The purpose of the present study was to examine the possible activation of the endogenous analgesic system in Leporinus macrocephalus fish and to evaluate the modification of swimming activity induced by a nociceptive stimulus (i.e., a subcutaneous injection of 3% formalin) in fish that had previously been exposed to the CAS. The results show that formalin-mediated enhancement in swimming activity was significantly reduced after exposure to the CAS. This enhancement was blocked by naloxone (20mg/kg), which suggests that opioid signaling is involved. Therefore, we hypothesized that antinociceptive processes may occur in fish following exposure to a chemical substance that signals predation.