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Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Multidimensional models of pain processing distinguish the sensory, motivational, and affective components of the pain experience. Efforts to understand underlying mechanisms have focused on isolating the roles of specific brain structures, including both limbic and non-limbic cortical areas, in the processing of nociceptive stimuli. The purpose of this study was to examine the role of the somatosensory cortex in both sensory and affective aspects of pain processing. It was hypothesized that animals with lesions of the hind limb area of the somatosensory cortex would demonstrate altered sensory processing (asomaesthesia, a deficit in the ability to detect and identify somatic sensation) in the presence of an inflammatory state when compared to animals with sham lesions. The level of pain affect produced by an inflammatory pain condition was not expected to change, as this region has not demonstrated a role in processing the affective component of pain. Seventy-nine adult female Sprague-Dawley rats were randomly assigned to receive bilateral lesions or a sham procedure. The results showed that somatosensory lesions to the hindlimb region altered responses to mechanical stimulation in the presence of experimentally-induced inflammation, but did not attenuate the inflammation-induced paw volume changes or the level of pain affect, as demonstrated by escape/avoidance behavior in response to mechanical stimulation. Overall, these results support previous evidence suggesting that the somatosensory cortex is primarily involved in the processing the sensory/discriminative aspect of pain, and the current study is the first to demonstrate the presence of pain affect in the absence of somatosensory processing., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The place escape/avoidance paradigm (PEAP) is a behavioral test designed to quantify the level of unpleasantness evoked by painful stimuli by assessing the willingness of a subject to escape/avoid a preferred area when it is associated with noxious stimulation. Previous studies have demonstrated that escape/avoidance behavior is dependent on activity in the anterior cingulate cortex (ACC), a region of the limbic system involved in processing the emotional component of pain in humans and animals. Analysis of c-Fos expression in the ACC confirmed that the escape/avoidance response to noxious stimuli corresponds to changes in neural activation in this region. Behavioral tests such as the PEAP may be more sensitive to changes in supraspinal pain processing and could contribute to the development of novel analgesics in the future., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The overall impact of chronic pain on the response to opioids is ambiguous in the literature, and comparisons between human and animal studies are complicated by vast differences between the manner and dosage of opioids given to humans treated for pain in comparison to rodents as well as a lack of healthy participant studies examining the impact of chronic opioids. The purpose of this study was to evaluate the impact of chronic pain on the development of tolerance to morphine and to assess how the concentration of drug affects this process. Twenty-four hours after the injection of CFA or normal saline in the left hind paw, the level of mechanical hypersensitivity was assessed and animals were randomly assigned to a morphine dose (1, 3 or 8 mg/kg or saline). Morphine was administered by subcutaneous injection twice a day for 5 days. On Day 6, animals were challenged with a single dose of 3 mg/kg morphine prior to formalin testing. Evidence of tolerance was mixed, and the results varied widely among the conditions. Analysis of mean paw withdrawal thresholds indicated that the analgesic efficacy of subcutaneous morphine diminished following repeated dosing. The presence of the chronic inflammatory pain condition during the morphine dosing period produced an increase in formalin pain behaviors compared to saline controls, such that animals given any dose of morphine during the 5-day dosing period showed higher responding to formalin following the 3 mg/kg dose than animals that had received saline injections. These results indicate that chronic pain does influence the development of opioid tolerance, but it does not prevent this phenomenon from occurring as suggested by some researchers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The purpose of the current study was to examine pain processing in adult rats following repeated maternal separation in infancy, a common model of early life stress. Sensory pain processing remained unaltered, as measured using threshold testing of nociception. However, affective pain processing was enhanced as revealed by increased responding during the tonic phase of the formalin test and during the place escape/avoidance test. The pattern of enhanced responses suggests that early life stress alters the emotional response to pain. Further research could determine if this pattern holds true for different pain models, or if post-weaning enrichment could reverse the effects of maternal separation on pain processing., (Copyright 2010 Elsevier B.V. All rights reserved.)

The non-specific opioid antagonist naltrexone has traditionally been used as treatment for opioid overdose, as well as in research settings as an antagonist to examine opioid and non-opioid mediated analgesia. However, the mechanisms by which this drug operates are not well understood, and its exact effects on sensory and affective pain processes remain uncertain. Various studies have demonstrated that naltrexone behaves in a paradoxical manner, leading to analgesia, no discernable changes, or an increase in pain, depending on the circumstances of the study. This imprecise spectrum of effects leads to difficulty in interpreting results in studies where naltrexone was utilized as an antagonist. Therefore, the purpose of this experiment was to further examine whether naltrexone elicits dose-dependent effects in behavioral tests designed to quantify the sensory and affective components of pain. Naltrexone was not expected to have an effect on carrageenan-induced inflammatory pain in sensory pain measures, but a dose-dependent increase was predicted in behavior related to the affective component of pain. Eighty-eight male Sprague-Dawley rats were used to test these hypotheses by measuring Mechanical Paw Withdrawal Thresholds before and after naltrexone injection and by assessing performance in the Place Escape Avoidance Paradigm test, a novel paradigm to test pain affect, in which naltrexone had not been utilized. The results demonstrated that naltrexone failed to increase place/escape avoidance behavior as anticipated, but rather produced a slight, but non-significant, decrease in escape avoidance behavior. Further research is needed to elucidate the differential effects of naltrexone on various aspects of pain-related behavior.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B , TNF , CXCL14 and OSM in male and CCL1 , CCL21 , PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Coexpression modules revealed enrichment in members of JUN-FOS signalling in males and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM , LIF , SOCS1) and females (CCL1 , CCL19 , CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations. [ABSTRACT FROM AUTHOR]

The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30–150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer’s and Parkinson’s disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics. [ABSTRACT FROM AUTHOR]

Background Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. Methods After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. Results A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. Conclusions Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use. [ABSTRACT FROM AUTHOR]

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents. [ABSTRACT FROM AUTHOR]

Abstract: Hyperbaric oxygen (HBO) treatment has been used clinically to treat a variety of ailments, including severe burns and carbon monoxide poisoning, and in research settings has produced promising results when used to treat animal models of inflammatory pain. However, studies examining neuropathic pain or nerve injury models have been limited to physiological assessments and not whether the pain condition improves. The purpose of this study was to evaluate the effect of HBO on two common models of neuropathic pain, L5 ligation and chronic constriction injury (CCI) of the sciatic nerve. Following surgical manipulations, animals demonstrating mechanical hyperalgesia were randomly assigned to either HBO treatment or control for 90min treatment sessions, after which mechanical sensitivity was assessed at 15min and 6h post. Daily HBO sessions, with assessments 15min post-treatment, continued for two weeks, followed by 5 days of assessment only. The results indicated that both models demonstrated significant improvement in response to treatment over the course of the two-week period, with CCI animals recovering more quickly and maintaining this recovery throughout the post-treatment period. Hyperbaric oxygen treatment appears to be successful in relieving neuropathic pain for an extended period of time, and future research should be aimed at investigating the precise mechanisms underlying this positive effect. [Copyright &y& Elsevier]

Abstract: The purpose of this project was to explore the role of the medial thalamus (MT), including the medial dorsal thalamus (MD) and associated midline nuclei in pain processing. Experiment 1 explored the role of electrolytic lesions to the MT in the formalin test. It was hypothesized that animals with electrolytic lesions to the MT would have attenuated paw licking behavior during the second phase of the formalin tests as compared to sham lesion controls. This hypothesis was based on evidence of projections from the MD to the ACC, and previous research demonstrating attenuation of paw licking behavior in the second phase of the formalin test in animals with ACC lesions. Experiment 2 tested the effects of electrolytic MT lesions on mechanical paw withdrawal thresholds in the L5 nerve ligation model. It was hypothesized that lesions of the MT would not alter mechanical paw withdrawal thresholds. Experiment 3 tested the effects of electrolytic MT lesions on escape/avoidance behavior in the place escape avoidance paradigm. For experiment 1, animals with MT lesions were found to have slightly elevated paw licking behavior, but only across two time points. No differences in mechanical paw withdrawal thresholds and in escape/avoidance behavior were detected as compared to the sham lesion group. These results indicate a limited role for the medial thalamic nuclei in coding for pain intensity and the affective dimension of pain. Additional research is needed to explore the role of individual medial nuclei in pain processing. [Copyright &y& Elsevier]