Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain.

Drug treatments for pain often do not outperform placebo, and a better understanding of placebo mechanisms is needed to improve treatment development and clinical practice. In a large-scale fMRI study (N = 392) with pre-registered analyses, we tested whether placebo analgesic treatment modulates nociceptive processes, and whether its effects generalize from conditioned to unconditioned pain modalities. Placebo treatment caused robust analgesia in conditioned thermal pain that generalized to unconditioned mechanical pain. However, placebo did not decrease pain-related fMRI activity in brain measures linked to nociceptive pain, including the Neurologic Pain Signature (NPS) and spinothalamic pathway regions, with strong support for null effects in Bayes Factor analyses. In addition, surprisingly, placebo increased activity in some spinothalamic regions for unconditioned mechanical pain. In contrast, placebo reduced activity in a neuromarker associated with higher-level contributions to pain, the Stimulus Intensity Independent Pain Signature (SIIPS), and affected activity in brain regions related to motivation and value, in both pain modalities. Individual differences in behavioral analgesia were correlated with neural changes in both modalities. Our results indicate that cognitive and affective processes primarily drive placebo analgesia, and show the potential of neuromarkers for separating treatment influences on nociception from influences on evaluative processes.

The effect of somatic pain and comorbid mental distress on oral health-related quality of life in orthodontic patients.

OBJECTIVES: The purpose of the present study was to evaluate the prevalence of somatic pain in orthodontic patients and determine whether somatic pain contributes to worsening oral health-related quality of life (OHRQoL) through the mediating effect of psychological discomfort. MATERIALS AND METHODS: Scale measurements and analyses were conducted on a cohort of 769 orthodontic outpatients, encompassing Patient Health Questionnaire-15-pain (PHQ-15-P), Hua-Xi Emotional-Distress Index (HEI), Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: Among the respondents, 56.3% (N = 433) reported somatic pain and 20.0% (N = 154) had mental discomfort based on PHQ-15-P and HEI scores. Patients with somatic pain symptoms had significantly higher scores of HEI and OHIP-14 (P < 0.001), and higher PHQ-15-P and HEI scores emerged as statistically significant predictors of lower OHIP-14 scores (P < 0.001). HEI scores which assessed anxiety and depression partially mediated the correlation between PHQ-15-P and OHIP-14 scores, of which anxiety accounted for 52.9% of the overall mediation effect, dominating the indirect effect. CONCLUSION: Orthodontic patients reporting somatic pains were at a significantly higher risk of worsening OHRQoL during treatment, and this adverse effect is partially mediated by anxiety and depression. CLINICAL RELEVANCE: Our findings highlight the necessity for the assessment of general health and mental well-being during orthodontic interventions. To prevent delays in treating general disorders and the potential failure of orthodontic treatments, we encourage increased attentiveness towards patients with somatic symptoms and consideration of the adverse effects of comorbid mental distress.

Comprehensive Targeted Treatment for Neuropathic and Nociceptive Pain in Palliative Care Patients.

BACKGROUND: Pain is a common symptom in patients with advanced, metastatic, or terminal cancer. Neuropathic pain and psycho-emotional suffering are factors that increase the difficulty of pain management. Pain control in patients with cancer remains a challenge for medical professionals. STUDY QUESTION: What is the evolution of neuropathic/mixed pain compared with nociceptive pain under standardized treatment in patients with cancer? STUDY DESIGN: A prospective, longitudinal, open-label, nonrandomized study was conducted on patients with cancer pain. MEASURES AND OUTCOMES: Pain type was assessed at admission using the modified Brief Pain Inventory, and pain intensity was assessed daily using the Numerical Rating Scale for 14 days and on days 21 and 28. Screening of depression was performed on days 1, 7, 14, 21, and 28 using the Hamilton Depression Rating Scale. Patients with pain and depression received analgesics with antidepressants, while patients without depression received analgesics or analgesics with an anticonvulsant depending on the pain subtype. RESULTS: Of 72 patients, 23 had nociceptive pain and 49 had neuropathic/mixed pain. At admission, pain intensity was higher for patients with neuropathic/mixed pain compared with nociceptive pain (mean values: 7.06 vs. 5.82) with statistical significance ( P = 0.001) and remained as such at the end of this study (mean values: 3.77 vs. 2.73). A decrease in the mean pain intensity was observed in all types of pain, but without statistical significance regardless of pain type and treatment protocol used ( P = 0.77). If depression was present, antidepressants combined with analgesics decreased pain and depression scores significantly ( P = 0.001). CONCLUSIONS: Patients with neuropathic/mixed pain have higher levels of pain and lower response to treatment. Identifying psycho-emotional suffering can improve pain control by intervening in the physical and psycho-emotional components of pain.

Comparison of Pain in Male Drug Rehabilitees with and without Human Immunodeficiency Virus in Yunnan Province, China.

BACKGROUND The purpose of this study was to compare pain symptoms in drug rehabilitees with or without human immunodeficiency virus (HIV) in Yunnan Province, China. MATERIAL AND METHODS This was a retrospective single-center cohort study. A total of 120 male substance users, including 65 with HIV, were enrolled after admission to the Fifth Drug Rehabilitation Center in Yunnan Province. Individuals who were >18 years of age and who had illicit drugs detected in their urine, despite not having used drugs for at least 2 months, were included. The patients evaluated their average pain intensity for the previous 4 weeks using a visual analog scale. PainDETECT questionnaire scores were used to classify pain into nociceptive and mixed component subgroups. Sleep quality was also evaluated using the Pittsburgh Sleep Quality Index scale. RESULTS The prevalence and intensity of the pain symptoms were higher for the drug rehabilitees with HIV than for those without HIV. Moreover, the rehabilitees with HIV were more likely to experience neuropathic and nociceptive pain, whereas those without HIV reported only nociceptive pain. The sleep quality of the rehabilitees with HIV was also lower, regardless of the pain symptoms. CONCLUSIONS Our results showed that the drug rehabilitees with HIV in Yunnan Province, China, experienced more frequent and stronger pain (both nociceptive and neuropathic) than those without HIV. They also experienced poorer sleep quality, although it was unrelated to pain. Our results provide data to support clinical diagnosis and treatment.

Give me a pain that I am used to: distinct habituation patterns to painful and non-painful stimulation.

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review.

A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new "antiaddiction" ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition-creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein-biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.

Prior Pain Exposure and Mere Possession of a Placebo Analgesic Predict Placebo Analgesia: Findings From a Randomized, Double-Blinded, Controlled Trial.

A recent study found that merely possessing a placebo analgesic reduces pain. The current study tested for a possible moderator of this effect. Specifically, does the mere possession of a placebo analgesic affect pain for individuals with and without immediate prior experience with the pain task? Healthy participants (N = 127) were randomized to prior pain (PP) condition or without prior pain (No-PP) condition. In the PP condition, participants first did a preliminary trial of a cold pressor test (CPT) to induce direct experience with this pain stimulus. Then they were randomized to possess an inert cream described as either an analgesic cream or an anti-itch cream (pain-irrelevant control object). Participants then completed the main CPT. In the No-PP condition, participants underwent identical procedures and randomization except that they did not do a preliminary CPT, thus having no immediate prior CPT pain experience. We found a significant prior pain experience and possession status interaction effect on placebo analgesia. Participants in the No-PP condition showed evidence of lower pain when they merely possessed an analgesic cream than an anti-itch cream. Such mere possession effect was not found in the PP condition. The impact of expectancy and emotion on the underlying process are discussed. PERSPECTIVE: This article presents a novel finding that prior pain exposure and mere possession of a placebo analgesic predicted placebo analgesia. It offers a novel perspective on the time course of placebo effect. It provides practical implications on potential pain intervention for clinicians and paradigm design for researchers of placebo study.

Pain management in hidradenitis suppurativa and a proposed treatment algorithm.

Pain contributes substantially to reduced quality of life in individuals living with hidradenitis suppurativa (HS). Although improved understanding of HS pathogenesis and treatment has resulted in improved evidence-based HS management guidelines, comprehensive pain management guidelines have yet to be developed. Few HS-specific data exist to guide pharmacologic analgesia; however, recognizing HS pain as either acute or chronic and predominantly nociceptive (aching and gnawing pain due to tissue damage) versus neuropathic (burning-type pain due to somatosensory nervous system dysfunction) provides a conceptual framework for applying outside pain management practices to HS management. This article incorporates the best available evidence from the HS and pain literature to propose an HS pain algorithm that integrates psychological, pharmacologic, and complementary and alternative treatment modalities.

Nociceptive, emotional, electrophysiological, and histological characterization of the chronic constriction injury model in female Wistar Han rats.

Chronic neuropathic pain affects 7-10 % of the population and is often accompanied by comorbid emotional disorders, which greatly reduce the quality of life of the patients, impairing physical, cognitive, emotional, and social functioning. Despite the higher prevalence and severity of chronic pain in women, the number of publications using female animals remains scarce. While in the chronic constriction injury (CCI) model the development of mechanical/thermal hyperalgesia, allodynia and spontaneous pain has been shown in both sexes, little is known on CCI-induced emotional impairments and sciatic nerve histopathology in female rats, as well as on the contributions of ovarian hormones to peripheral nerve injury. In this work, young adult rats (Wistar Han) were assigned to one of five groups: gonadally intact females (SHAM/SHAM), ovariectomized females (SHAM/OVX), gonadally intact females with CCI (CCI/SHAM); ovariectomized females with CCI (CCI/OVX) and males with CCI (CCIM). In the postoperative period, CCI animals, both females and males, displayed visible gait abnormalities, limping and guarding the affected hind paw although locomotion was not affected. Neuropathic females developed sustained mechanical allodynia, with CCI/OVX animals displaying symptoms two weeks before CCI/SHAM females. Interestingly, regarding mechanical and cold allodynia, CCI males slowly recovered from week 3 onwards. While CCI induced neither anxiety- nor depressive-like behaviour in females, ovariectomy per se induced anhedonic-like behaviour, regardless of CCI surgery. Histopathological analysis of the sciatic nerve showed CCI induced nerve damage, fibrosis, myelin sheath degradation and inflammation. Single-cell electrophysiological data from the rostral ventromedial medulla (RVM) suggests this area is partly involved in descending facilitation associated with experimental neuropathic pain. Altogether, our findings demonstrate CCI females display distinct sensory, emotional, electrophysiological, and histopathological impairments from males, and that ovariectomy aggravates females' responses to peripheral nerve injury.

Changes in opioid receptors, opioid peptides and morphine antinociception in mice subjected to early life stress.

Recent studies have shown that the endogenous opioid system is considerably affected by early life stress such as child abuse. Here, we investigated whether early life stress changes the endogenous opioid receptors and their peptides, and if such stress impacts morphine antinociception. We used mice affected by maternal separation and social isolation (MSSI) as an early life stress model. In the tail-flick test, 10-week-old MSSI mice showed a significant decrease in morphine antinociception compared to age-matched control mice. The number of c-Fos-positive cells increased in the periaqueductal gray (PAG), nucleus accumbens, and thalamus of control mice after the morphine injections, whereas hardly any positive cells were detected in the same areas of MSSI mice. The expression of µ- and κ-opioid receptor (MOR and KOR, respectively) messenger RNA (mRNA) was significantly decreased in the PAG of MSSI mice, whereas KOR expression was significantly increased in the amygdala of MSSI mice. The expression of δ-opioid receptor (DOR) mRNA was significantly reduced in the PAG and rostral ventromedial medulla of MSSI mice compared to control mice. Moreover, the lack of morphine antinociception was observed in 18-week-old MSSI mice. Our findings suggest that the supraspinal opioid system may be affected by early life stress exposure, and that this exposure may impact morphine antinociception.

Mode of delivery alters dental pulp nociception and pain-induced changes in cognitive performance in adults male rats.

This study examined the effects of delivery mode on the response to inflammatory pulpal pain and pain-induced changes in cognitive performance in adult rats. Experiments were done on rats born by vaginal or caesarean section (C-section) delivery. Dental pulp was irritated by intradental capsaicin (100 µg) application and then nociceptive scores were recorded for 40 min. Spatial and passive avoidance learning and memory were assessed using the Morris water maze (MWM) and shuttle box tools, respectively. Additionally, in vivo recording of field excitatory postsynaptic potential (fEPSP) in the CA1 of the hippocampus was used to verify synaptic plasticity. Capsaicin produced more significant nociceptive behavior in vaginally delivered rats compared to C-section rats (P < 0.01). C-section-delivered rats show better performance in both MWM and shuttle box tests. Likewise, C-section rats had greater fEPSP slopes compared to the vaginally delivered group (P < 0.05). Capsaicin impairs cognitive performance in rats born by each delivery route. However, capsaicin effects were more significant in rats delivered vaginally than by C-section. Overall, C-section-delivered rats show lower sensitivity to capsaicin-evoked pulpal nociception and better cognitive performance than vaginally delivered rats. These effects are in part mediated by reduced neuroinflammation and enhanced neuronal synaptic plasticity following C-section delivery.

Local Anesthetic Injection Resolves Movement Pain, Motor Dysfunction, and Pain Catastrophizing in Individuals With Chronic Achilles Tendinopathy: A Nonrandomized Clinical Trial.

OBJECTIVES: Peripherally directed treatments (targeted exercise, surgery) can reduce, but not fully eliminate, pain for up to 40% of patients with Achilles tendinopathy. The objectives of the present study were (1) to identify indicators of altered central processing in participants with Achilles tendinopathy compared to controls, and (2) to determine which indicators of altered central processing would persist after a local anesthetic injection in patients with Achilles tendinopathy. DESIGN: Mechanistic clinical trial. METHODS: Forty-six adults (23 with chronic Achilles tendinopathy, 23 matched controls) repeated (1) a movement-evoked pain rating, (2) motor performance assessment, (3) pain psychology questionnaires, and (4) quantitative sensory testing. Participants with Achilles tendinopathy received a local anesthetic injection before repeat testing and controls did not. Mixed-effects analyses of variance examined the effects of group, time, and group by time. RESULTS: The Achilles tendinopathy group had movement-evoked pain, motor dysfunction, and higher pain psychological factors (pain catastrophizing, kinesiophobia) compared to controls (P<.05). The Achilles tendinopathy group did not have indicators of nociplastic pain with quantitative sensory testing (P>.05). In those with Achilles tendinopathy, local anesthetic injection eliminated pain and normalized the observed deficits in heel-raise performance and pain catastrophizing (group-by-time effect, P<.01), but not in kinesiophobia (P = .45). Injection did not affect measures of nociplastic pain (P>.05). CONCLUSION: People with Achilles tendinopathy had elevated pain psychological factors and motor dysfunction but no signs of nociplastic pain with quantitative sensory testing. Removal of nociceptive input normalized movement-evoked pain and some indicators of altered central processing (motor dysfunction, pain catastrophizing), but not kinesiophobia. J Orthop Sports Phys Ther 2020;50(6):334-343. Epub 29 Apr 2020. doi:10.2519/jospt.2020.9242.

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARß/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARß/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARß/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARß/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.

Pain is Associated With Increased Physical and Psychosocial Impairment in Youth With a History of Burn Injuries.

Burn injuries are significantly painful and associated with physical and psychological impairment. However, little research to-date has examined the potential role of the subjective experience of pain in either physical or psychological impairment in this population. This may be particularly important to examine, given that the pain experience can often be a significant barrier to recovery in other pediatric populations. The current study examined the cross-sectional and predictive relationships between patient-reported experience of pain (operationalized as PROMIS pain interference and self-reported pain intensity) and physical and psychosocial outcomes. Data were gathered as part of the Burn Model System National Database (1994-2018) with the data request inclusive of pediatric self-report PROMIS measures, child PTSD, and post-traumatic growth symptoms assessed at 6- and 12-month postdischarge following initial injury. A total of 65 youth between the ages of 6 and 16 years at the time of their injury were included in the dataset. Correlational and regression analyses indicated that pain interference was cross-sectionally and longitudinally associated with decreased physical functioning, depressive symptoms, and peer relationships. Pain intensity was significantly associated with and predictive of physical functioning and pain interference. Results of the current study are an important first step in understanding the pain experience and associated outcomes in youth with a history of burn injuries. Future research is needed to further examine these relationships. PERSPECTIVE: This study presents preliminary findings from a national database on pain-related outcomes both cross-sectionally and longitudinally in youth with a history of burn injury. To-date, pain-related outcomes are poorly understood in this population and the results of this study serve to inform future research and treatment-related efforts.

Cortisol affects pain sensitivity and pain-related emotional learning in experimental visceral but not somatic pain: a randomized controlled study in healthy men and women.

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

Family Strain, Depression, and Somatic Amplification in Adults with Chronic Pain.

BACKGROUND: The associations between family strain, depression, and chronic pain interference vary across individuals, suggesting moderated relations, and one possible moderator is somatic amplification. The current study examined a moderated mediation model that investigated (a) whether depression mediated the relation between non-spouse family strain and chronic pain interference and (b) whether somatic amplification moderated the association between depression and chronic pain interference. METHODS: Data came from 933 adults who participated in the National Survey of Midlife Development in the USA. Participants completed telephone interviews or self-report measures. RESULTS: The relationship between non-spouse family strain and chronic pain interference was mediated by depression, and this mediation depended on the degree of somatic amplification. Specifically, individuals who experienced more non-spouse family strain were more likely to experience depression and higher levels of chronic pain interference. Somatic amplification significantly moderated the effect of depression on chronic pain, such that individuals with higher levels of somatic amplification and depression were likely to experience higher levels of chronic pain interference. The indirect effect of non-spouse family strain on chronic pain through depression was significant for low, middle, and high levels of somatic amplification. CONCLUSIONS: The presence of chronic pain has been associated with family dynamics changing, which may be linked with higher levels of non-spouse family strain. A negative family environment may be related to the development of depression, which may be associated with the severity and inability to cope with chronic pain. Somatic amplification may strengthen the association between depression and pain intensity.

Evidence for the involvement of opioid and cannabinoid systems in the peripheral antinociception mediated by resveratrol.

Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception. Paw withdrawal method was used and hyperalgesia was induced by carrageenan (200 µg/paw). All drugs were given by intraplantar injection in male Swiss mice (n = 5). RES (100 µg/paw) administered in the right hind paw induced local antinociception that was antagonized by naloxone, non-selective opioid receptor antagonist, and clocinnamox, µOR selective antagonist. Naltrindole and nor-binaltorfimine, selective antagonists for δOR and kOR, respectively, did not reverse RES-induced peripheral antinociception. CB1R antagonist AM251, but not CB2R antagonist AM630, antagonized RES-induced peripheral antinociception. Peripheral antinociception of RES intermediate-dose (50 µg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of µOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through µOR and CB1R activation by endogenous opioid and endocannabinoid releasing.

Multiple types of somatic pain increase suicide attempts and depression: A nationwide community sample of Korean adults.

OBJECTIVE: Somatic pain is an important risk factor for suicide and suicidal behaviors. However, the association between the number of somatic pain conditions and lifetime suicide attempts (LSA) has not been well established yet. Therefore, the objective of this study was to examine associations between LSA and multiple somatic pain (MSP), singe pain, and no pain in a nationwide survey. METHODS: A total of 12,532 adults were randomly selected from the population using the one-person-per-household method. Each participant completed a face-to-face interview using the Korean Composite International Diagnostic Interview (K-CIDI) with Suicide Module, and the Barratt Impulsiveness Scale 11 (BIS-11). The MSP was defined as pain in two or more parts of one's body, including abdominal pain, back pain, arthralgia, arm or leg pain, chest pain, headache, menstrual pain, dysuria, genital pain, and other pain. RESULTS: Among 12,532 subjects, 858 (6.85%) had MSP. Among the three groups (MSP, single pain, and no pain) of subjects, the MSP group had higher percentages of females, those with lower education, and divorced/widowed/separated individuals. However, there were no significant differences in monthly income or residence among the three groups. The MSP group showed four times higher suicide attempts and six times higher multiple attempts than did the no pain group. The BIS total score of the MSP group was the highest among the three groups. Genital pain showed the highest odds ratio for LSA. The higher the number of somatic pain, the higher the odds ratios were for LSA, major depressive disorder (MDD), and anxiety disorders. Subjects having both MSP and MDD showed a significant association with LSA (AOR = 14.78, 95% CI 10.08-21.67, p < 0.001) compared to those having neither somatic pain nor MDD. CONCLUSIONS: MSP was significantly associated with LSA. It had greater prevalence among individuals reporting a higher number of somatic pain conditions and comorbid MDD.

Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain.

Neuropathic pain is a complex disorder associated with emotional and cognitive deficits that may impair nociceptive manifestations. There is high inter-individual variability in the manifestations of human neuropathic pain, which largely depends on personality traits. We aim to identify the influence of different behavioral traits in the inter-individual vulnerability to neuropathic pain manifestations using behavioral, electrophysiological and genetic approaches. We first selected mice with extreme social and emotional traits and look for correlation with the spontaneous neuronal activity in the central amygdala. Neuropathic pain was induced to these mice to evaluate the influence of behavioral traits on nociceptive manifestations and gene expression profiles in the amygdala. Our results show an association of the spontaneous central amygdala neuronal activity with the sociability behavior. We demonstrate that low sociable, high anxious and low depressive phenotypes develop enhanced nociceptive hypersensitivity after nerve injury. However, greater emotional alterations and cognitive impairment are observed in high sociable, anxious-like and depressive-like mice, indicating that nociceptive, emotional and cognitive manifestations of neuropathic pain do not correlate with each other. Gene analyses identify high Pdyn and Il6 levels in the amygdala as indicative of enhanced nociceptive hypersensitivity and reveal an association between high Gadd45 expression and attenuated emotional and cognitive manifestations of neuropathic pain.