Chronic restraint stress-induced hyperalgesia is modulated by the periaqueductal gray neurons projecting to the rostral ventromedial medulla in mice.

Stress-induced hyperalgesia (SIH) is induced by repeated or chronic exposure to stressful or uncomfortable environments. However, the neural mechanisms involved in the modulatory effects of the periaqueductal gray (PAG) and its associated loops on SIH development hav e not been elucidated. In the present study, we used chronic restraint stress (CRS)-induced hyperalgesia as a SIH model and manipulated neuronal activity via a pharmacogenetic approach to investigate the neural mechanism underlying the effects of descending pain-modulatory pathways on SIH. We found that activation of PAG neurons alleviates CRS-induced hyperalgesia; on the other hand, PAG neurons inhibition facilitates CRS-induced hyperalgesia. Moreover, this modulatory effect is achieved by the neurons which projecting to the rostral ventromedial medulla (RVM). Our data thus reveal the functional role of the PAG-RVM circuit in SIH and provide analgesic targets in the brain for clinical SIH treatment.

Activation of CRF/CRFR1 Signaling in the Central Nucleus of the Amygdala Contributes to Chronic Stress-Induced Exacerbation of Neuropathic Pain by Enhancing GluN2B-NMDA Receptor-Mediated Synaptic Plasticity in Adult Male Rats.

Exacerbation of pain by chronic stress and comorbidity of pain with stress-related disorders such as depression and post-traumatic stress disorder, represent significant clinical challenges. Previously we have documented that chronic forced swim (FS) stress exacerbates neuropathic pain in spared nerve injury (SNI) rats, associated with an up-regulation of GluN2B-containing N-methyl-D-aspartate receptors (GluN2B-NMDARs) in the central nucleus of the amygdala (CeA). However, the molecular mechanisms underlying chronic FS stress (CFSS)-mediated exacerbation of pain sensitivity in SNI rats still remain unclear. In this study, we demonstrated that exposure of CFSS to rats activated the corticotropin-releasing factor (CRF)/CRF receptor type 1 (CRFR1) signaling in the CeA, which was shown to be necessary for CFSS-induced depressive-like symptoms in stressed rats, and as well, for CFSS-induced exacerbation of pain hypersensitivity in SNI rats exposed to chronic FS stress. Furthermore, we discovered that activation of CRF/CRFR1 signaling in the CeA upregulated the phosphorylation of GluN2B-NMDARs at tyrosine 1472 (pGluN2BY1472) in the synaptosomal fraction of CeA, which is highly correlated to the enhancement of synaptic GluN2B-NMDARs expression that has been observed in the CeA in CFSS-treated SNI rats. In addition, we revealed that activation of CRF/CRFR1 signaling in the CeA facilitated the CFSS-induced reinforcement of long-term potentiation as well as the enhancement of NMDAR-mediated excitatory postsynaptic currents in the basolateral amygdala (BLA)-CeA pathway in SNI rats. These findings suggest that activation of CRF/CRFR1 signaling in the CeA contributes to chronic stress-induced exacerbation of neuropathic pain by enhancing GluN2B-NMDAR-mediated synaptic plasticity in rats subjected to nerve injury. PERSPECTIVE: Our present study provides a novel mechanism for elucidating stress-induced hyperalgesia and highlights that the CRF/CRFR1 signaling and the GluN2B-NMDAR-mediated synaptic plasticity in the CeA may be important as potential therapeutic targets for chronic stress-induced pain exacerbation in human neuropathic pain. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Sex differences in stress-induced hyperalgesia and its mechanisms.

Chronic stress induces a variety of physiological and/or psychological abnormalities, including hyperalgesia. Researchers have discovered sex differences in the prevalence of stress-induced hyperalgesia (SIH) in recent years. Sex differences may be one of the reasons for the heterogeneity of susceptibility to stress-related diseases. In this review, the potential mechanisms of sex differences in SIH are discussed, such as hypothalamus-pituitary-adrenal axis responses, regulation of sex hormones, and immune system responses.

miR­3120/Hsc70 participates in forced swim stress­induced mechanical hyperalgesia in rats in an inflammatory state.

The heat shock cognate 71 kDa protein (Hsc70) is a stress­inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well­documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress­induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)­3120 were investigated in forced swim (FS) stress­induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS + CFA rats, FS stress was performed for 3 days before CFA injection. The levels of Hsc70, miR­3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription­quantitative polymerase chain reaction and fluorescence in situ hybridization. The results revealed that FS stress significantly exacerbated CFA­induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS + CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV­Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR­3120, a regulator of Hsc70, were markedly upregulated on day 3 following FS stress. Finally, miR­3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR­3120 agomir to induce overexpression of miR­3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV­Hsc70. These findings suggested that miR­3120/Hsc70 may participate in FS stress­induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.

The Role of The Rostral Ventromedial Medulla in Stress Responses.

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders.

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Bone marrow mesenchymal stem cells alleviate stress-induced hyperalgesia via restoring gut microbiota and inhibiting neuroinflammation in the spinal cord by targeting the AMPK/NF-κB signaling pathway.

Aim Spinal neuroinflammation contributes to the mechanism of stress-induced hyperalgesia (SIH). Recent research has demonstrated that bone marrow mesenchymal stem cells (BMSCs) alleviate chronic pain. However, what remains unidentified is whether BMSCs could improve hyperalgesia induced by chronic restraint stress (CRS). In another dimension, our previous study proved that gut microbiota played an important role in CRS-induced hyperalgesia in mice. Yet, whether BMSCs treatments change gut microbiota composition in CRS mice remains unexplored. MAIN METHODS: Mechanical allodynia and thermal hyperalgesia were used to assess pain behavior. Composition of fecal samples were verified by 16S rRNA analysis. Western blot was used to investigate the expression of adenosine monophosphate-activated protein kinase (AMPK)/ nuclear factor kappa B (NF-κB) signaling pathway, pro-inflammatory cytokines [interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), IL-6], and the markers of microglia and astrocytes. The morphology of glia cells was evaluated by immunofluorescence staining. KEY FINDINGS: CRS down-regulated phosphorylated AMPK (p-AMPK), up-regulated phosphorylated NF-κB p65 (p-NF-κB p65), activated microglia and astrocytes and promoted the secretion of IL-1ß, TNF-α and IL-6 in the spinal cord. BMSCs alleviated CRS-induced hyperalgesia by inhibiting the activation of microglia and astrocytes and by reducing neuroinflammation via improving the disrupted AMPK/NF-κB pathway. Furthermore, BMSCs also raised the relative abundance of Muribaculaceae and Lachnospiraceae in CRS mice feces, which was significantly related to its effect of relieving hyperalgesia. SIGNIFICANCE: Our results support that BMSCs could alleviate CRS-induced hyperalgesia by reducing AMPK/NF-κB-dependent neuroinflammation in the spinal cord and restoring the homeostasis of gut microbiota.

Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites.

Long-term stress causes hyperalgesia; and there are gender differences in the mechanism of pain in male and female individuals. The role of gut microbiota in pain has also been verified. However, whether gut microbiota plays a role in hyperalgesia caused by chronic restraint stress (CRS) with gender differences has not been explored. This study investigated the role of gut microbiota in CRS-induced hyperalgesia gender-specifically through 16 S ribosomal RNA (16 S rRNA) gene sequencing and untargeted metabolomic analysis using liquid chromatography-mass spectrometry (LC-MS). The study found that both male and female mice experienced hyperalgesia after CRS and antibiotic treatment. 16 S rRNA gene sequencing reveals gender differences in the fecal microbiota induced by CRS. The pain threshold decreased after transplanting the fecal microbiota from the male and female CRS group to the corresponding pseudo-germ-free mice. In addition, this study detected gender differences in the host gut microbiota and serum metabolism induced by fecal microbiota transplantation (FMT). Specifically, the different serum metabolites between the pseudo-germ-free mice receiving FMT from the CRS group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice. In summary, the gut microbiota participates in stress-induced hyperalgesia (SIH) with gender differences by influencing the host's gut microbiota composition and serum metabolism. Therefore, our findings provided insights into developing novel gut microbiota-associated drugs for the management of gender-specific SIH.

Angiotensin II type 1 receptor blockade attenuates posttraumatic stress disorder-related chronic pain by inhibiting glial activation in the spinal cord.

Clinically, posttraumatic stress disorder (PTSD) and chronic pain are highly comorbid conditions, but the underlying mechanisms of and therapeutic strategies against PTSD-related pain remain unclear. Our previous studies suggested that dysregulation of neuroinflammation contributes to the development of stress-induced hyperalgesia. Recent studies reported that angiotensin II was a 'stress-related hormone', and could induce glial activation by stimulating the type 1 receptor (AT1R). In the present study, we aimed to investigate whether AT1R blockade could attenuate mechanical allodynia induced by PTSD-like stress. Adult male rats were exposed to single prolonged stress (SPS) to establish a model of PTSD-pain comorbidity. Our results showed that SPS exposure increased the levels of angiotensin II in the hippocampus, prefrontal cortex (PFC) and spinal cord; intraperitoneal injection of losartan attenuated SPS-induced mechanical allodynia, and suppressed SPS-induced glial activation (both microglia and astrocytes) and proinflammatory cytokine expression in the PFC and spinal cord, but not in the hippocampus. We further showed that intrathecal injection of losartan also exerted anti-hyperalgesic effect and suppressed SPS-induced glial activation and proinflammatory cytokine expression in the spinal cord. These results indicated that AT1R blockade by losartan attenuated mechanical allodynia induced by PTSD-like stress, and this may be attributed to the suppression of glial activation and proinflammatory cytokine expression in the spinal cord. Although further research is warranted to verify our findings in female rodents and to assess pharmacological effects of AT1R blockade in PFC and hippocampus, our study suggested the therapeutic potential of targeting AT1R in the treatment of PTSD-related chronic pain.

Nitric Oxide in the Spinal Cord Is Involved in the Hyperalgesia Induced by Tetrahydrobiopterin in Chronic Restraint Stress Rats.

It has been well recognized that exposure to chronic stress could increase pain responding and exacerbate pain symptoms, resulting in stress-induced hyperalgesia. However, the mechanisms underlying stress-induced hyperalgesia are not yet fully elucidated. To this end, we observed that restraint as a stressful event exacerbated mechanical and thermal hyperalgesia, accompanied with up-regulation of nitric oxide (NO) (P < 0.001), GTP cyclohydrolase 1 (GCH1) (GCH1 mRNA: P = 0.001; GCH1 protein: P = 0.001), and tetrahydrobiopterin (BH4) concentration (plasma BH4: P < 0.001; spinal BH4: P < 0.001) on Day 7 in restraint stress (RS) rats. Intrathecal injection of N ω-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase inhibitor, or N-([3-(aminomethyl)phenyl]methyl) ethanimidamide, a special inhibitor of inducible NO synthase (iNOS), for seven consecutive days attenuated stress-induced hyperalgesia and decreased the production of NO (P < 0.001). Interestingly, 7-nitro indazole, a special inhibitor of neuronal NO synthase, alleviated stress-induced hyperalgesia but did not affect spinal NO synthesis. Furthermore, intrathecal injection of BH4 not only aggravated stress-induced hyperalgesia but also up-regulated the expression of spinal iNOS (iNOS mRNA: P = 0.015; iNOS protein: P < 0.001) and NO production (P < 0.001). These findings suggest that hyperalgesia induced by RS is associated with the modulation of the GCH1-BH4 system and constitutively expressed spinal iNOS. Thus, the GCH1-BH4-iNOS signaling pathway may be a new novel therapeutic target for pain relief in the spinal cord.

Acute elevated platform triggers stress induced hyperalgesia and alters glutamatergic transmission in the adult mice anterior cingulate cortex.

Pain is composed of both physiological and affective/emotional components which potentiate one another. In addition, exposure to stress modulates pain and affective behaviors including, anxiety-like behavior and/or depression-like behaviors. Indeed, chronic exposure to stress has been known to enhance stress-induced hyperalgesia (SIH). The anterior cingulate cortex (ACC) is critically involved in pain sensation and emotions. Animal models of chronic pain, but not acute nociception have been found to induce synaptic plasticity on glutamatergic and GABAergic transmission in the rodent ACC. However, it is unclear whether acute stress exposure could produce SIH and cause synaptic plasticity in the ACC. Accordingly, we studied how acute exposure of stress by the elevated open platform (EOP) could affect mechanical threshold, thermal and cold latency in the adult mice. Thirty minutes of the EOP produced mechanical hypersensitivity lasting for 60 min and thermal hypersensitivity immediately after the exposure. Next, we tested whether the stress could alter the excitatory and inhibitory synaptic transmission in the ACC. We performed whole-cell patch-clamp recordings from layer II/III pyramidal neurons in the ACC and analyzed both glutamatergic and GABAergic transmission in mice following the EOP. Thirty minutes of the EOP altered the rise and decay time of spontaneous glutamatergic AMPA/GluK receptors mediated currents, but did not change the frequency or amplitude of excitatory transmission. By contrast, the kinetics of inhibitory synaptic currents were not altered by the EOP. These results suggest that acute stress by the elevated platform produces SIH and causes synaptic plasticity on excitatory transmission, but not inhibitory transmission in the ACC.

Chronic stress influences nociceptive sensitivity of female rats in an estrous cycle-dependent manner.

Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.SUMMARYOur studies showed that chronic stress increased nociceptive sensitivity of female rats. Furthermore females had different stress-induced pain responses in different estrous phases: mechanical hyperalgesia in proestrus and estrus, formalin-evoked acute hyperalgesia in metestrus and diestrus.

Perioperative activation of spinal α7 nAChR promotes recovery from preoperative stress-induced prolongation of postsurgical pain.

Preoperative stress could delay the recovery of postoperative pain and has been reported to be a risk factor for chronic postsurgical pain. As stress could facilitate the proinflammatory activation of microglia, we hypothesized that these cells may play a vital role in the development of preoperative stress-induced pain chronification after surgery. Our experiments were conducted in a rat model that consists of a single prolonged stress (SPS) procedure and plantar incision. A previous SPS exposure induced anxiety-like behaviors, prolonged incision-induced mechanical allodynia, and potentiated the activation of spinal microglia. Based on the results from ex vivo experiments, spinal microglia isolated from SPS-exposed rats secreted more proinflammatory cytokines upon challenge with LPS. Our results also demonstrated that microglia played a more important role than astrocytes in the initiation of SPS-induced prolongation of postsurgical pain. We further explored the therapeutic potential of agonism of α7 nAChR, an emerging anti-inflammatory target, for SPS-induced prolongation of postsurgical pain. Multiple intrathecal (i.t.) injections of PHA-543613 (an α7 nAChR agonist) or PNU-120596 (a type II positive allosteric modulator) during the perioperative period shortened the duration of postsurgical pain after SPS and suppressed SPS-potentiated microglia activation, but their effects were abolished by pretreatment with methyllycaconitine (an α7 nAChR antagonist; i.t.). Based on the results from ex vivo experiments, the anti-inflammatory effects of PHA-543613 and PNU-120596 may have been achieved by the direct modulation of microglia. In conclusion, stress-induced priming of spinal microglia played a key role in the initiation of preoperative stress-induced prolongation of postsurgical pain, and PHA-543613 and PNU-120596 may be potential candidates for preventing pain chronification after surgery.

Chronic stress increases pain sensitivity via activation of the rACC-BLA pathway in rats.

Exposure to chronic stress can produce maladaptive neurobiological changes in pathways associated with pain processing, which may cause stress-induced hyperalgesia (SIH). However, the underlying mechanisms still remain largely unknown. In previous studies, we have reported that the amygdala is involved in chronic forced swim (FS) stress-induced depressive-like behaviors and the exacerbation of neuropathic pain in rats, of which, the basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA) are shown to play important roles in the integration of affective and sensory information including nociception. Here, using in vivo multichannel recording from rostal anterior cingulate cortex (rACC) and BLA, we found that chronic FS stress (CFSS) could increase the pain sensitivity of rats in response to low intensity innoxious stimuli (LIS) and high intensity noxious stimuli (HNS) imposed upon the hindpaw, validating the occurrence of SIH in stressed rats. Moreover, we discovered that CFSS not only induced an increased activity of rACC neuronal population but also produced an augmented field potential power (FPP) of rACC local field potential (LFP), especially in low frequency theta band as well as in high frequency low gamma band ranges, both at the baseline state and under LIS and HNS conditions. In addition, by using a cross-correlation method and a partial directed coherence (PDC) algorithm to analyze the LFP oscillating activity in rACC and BLA, we demonstrated that CFSS could substantially promote the synchronization between rACC and BLA regions, and also enhanced the neural information flow from rACC to BLA. We conclude that exposure of chronic FS stress to rats could result in an increased activity of rACC neuronal population and promote the functional connectivity and the synchronization between rACC and BLA regions, and also enhance the pain-related neural information flow from rACC to BLA, which likely underlie the pathogenesis of SIH.

Stress-induced modulation of pain: Role of the endogenous opioid system.

Depending on its nature, duration, and intensity, stress can exert potent and bidirectional modulatory effects on pain, either reducing pain (stress-induced analgesia) or exacerbating it (stress-induced hyperalgesia). The descending pain pathway has been implicated in both stress-induced analgesia and stress-induced hyperalgesia. The endogenous opioid system is widely distributed throughout the descending pain pathway and regulates nociceptive signaling, emotionality, and the response to stress. Here we review the evidence for a key role of the endogenous opioid system in stress-induced modulation of pain in rodents and humans. Understanding the neurobiological mechanisms underlying opioidergic regulation of stress-pain interactions may help in identifying novel therapeutic strategies for the improved treatment of comorbid pain and stress-related disorders.

Somatosensory profiles of patients with chronic myogenic temporomandibular disorders in relation to their painDETECT score.

BACKGROUND: The purpose of this study was to characterize patients with chronic temporomandibular disorders (TMD) in terms of existing hyperalgesia against cold, heat and pressure. METHODS: The extent of hyperalgesia for pressure and thermal sensation in TMD patients was determined by the use of the painDETECT questionnaire ("Is cold or heat in this area occasionally painful?" "Does slight pressure in this area, e.g., with a finger, trigger pain?") and experimental somatosensory testing against thermal and pressure stimuli (Quantitative Sensory Testing; QST). In addition, we explored psychological comorbidity among the chronic TMD patients (hospital anxiety and depression scale, HADS-D and coping strategies questionnaire, CSQ). RESULTS: Nineteen patients with chronic TMD and 38 healthy subjects participated in the study. N = 12 patients had a painDETECT score ≤ 12, n = 3 patients had a painDETECT score of 13-18 and n = 4 patients had a painDETECT score ≥ 19. TMD patients with painDETECT scores ≥19 had moderately, strong or very strong enhancement of thermal and pressure pain perception, whereas patients with painDETECT scores 13-18 and ≤ 12 responded these questions with "never", "hardly noticed" or "slightly painful" (p < 0.05-0.01). With increasing painDETECT scores we found increased hyperalgesia for pressure (p < 0.01) and thermal stimuli (p < 0.05) in QST. The patients with a painDETECT score ≥ 19 showed increased signs of anxiety (p < 0.05), depression (p < 0.01), praying and hoping (p < 0.05). CONCLUSION: The present study has shown that the PainDETECT questionnaire can be a helpful additional diagnostic tool. Together with QST, the PainDETECT questionnaire detected hyperalgesia for pressure and thermal sensation. Therefore the PainDETECT questionnaire is helpful to decide which TMD patients should undergo QST.

The role of glutamate and its receptors in central nervous system in stress-induced hyperalgesia.

PURPOSE: To explore the potential mechanisms of glutamate and its receptors in stress-induced hyperalgesia. MATERIALS AND METHODS: The stress-induced hyperalgesia, glutamate and its receptors are listed as key items in the pubmed database and the related articles are searched. RESULTS: Glutamate level is increased under stress and associated with stress-induced hyperalgesia. Moreover, the role of glutamate in stress-induced hyperalgesia depends on its subtypes of its receptors. CONCLUSIONS: Increased glutamate during stress connect with ionotropic glutamate receptors can prompt hyperalgesia, but connect with metabotropic glutamate receptors can inhibit hyperalgesia.

The cannabinoid system and pain.

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Spinal activation of alpha7-nicotinic acetylcholine receptor attenuates posttraumatic stress disorder-related chronic pain via suppression of glial activation.

The high prevalence of chronic pain in posttraumatic stress disorder (PTSD) individuals has been widely reported by clinical studies, which emphasized an urgent need to uncover the underlying mechanisms and identify potential therapeutic targets. Recent studies suggested that targeting activated glia and their pro-inflammatory products may provide a novel and effective therapy for the stress-related pain. In this study, we investigated whether activation of alpha-7 nicotinic acetylcholine receptor (α7 nAChR), a novel anti-inflammatory target, could attenuate PTSD-related chronic pain. The experiments were conducted in a rat model of single prolonged stress (SPS), an established model of PTSD-pain comorbidity. We found that SPS exposure produced persistent mechanical allodynia. Immunohistochemical and enzyme-linked immuno sorbent assay analysis showed that SPS also induced elevated activation of glia cells (including microglia and astrocytes) and accumulation of pro-inflammatory cytokines in spinal cord. In another experiment, we found that intrathecal injection of PHA-543613, a selective α7 nAchR agonist, attenuated the SPS-evoked allodynia in a dose dependent manner. However, this anti-hyperalgesic effect was blocked by pretreatment with methyllycaconitine (MLA), a selective α7 nAchR antagonist. Further analyses showed that PHA-543613 suppressed SPS-induced spinal glial activation and SPS-elevated spinal pro-inflammatory cytokines, and these were abolished by MLA. Taken together, the present study showed that spinal activation of α7 nAChR by PHA-543613 attenuated mechanical allodynia induced by PTSD-like stress, and the suppression of spinal glial activation may underlie this anti-hyperalgesic effect. Our study demonstrated the therapeutic potential of targeting α7 nAChR in the treatment of PTSD-related chronic pain.