Our previous study demonstrated an increase in α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor sensitivity in the rostral ventromedial medulla (RVM) associated with enhanced net ...descending inhibition after inflammatory hyperalgesia. The present study further studied the time-dependent changes in AMPA-produced inhibition after inflammation and the underlying molecular mechanisms. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA, 0.2
ml). There was a significant increase in AMPA-produced inhibition at 5
h that was further enhanced at 24
h (
P<0.05), as compared to that at 3
h post-inflammation. The AMPA-produced inhibition returned to the control level at 14 days post-inflammation. We analyzed mRNA and protein levels of the GluR1 and GluR2 AMPA receptor subunits in the RVM at 2
h to 14 days post-inflammation. AMPA receptor subunits exist in the two ‘flip’ and ‘flop’ isoforms that differentially affect the desensitization properties of the receptor. Reverse transcription-polymerase chain reaction analysis indicated that there was a significant upregulation of mRNAs encoding the GluR1-flip (5–24
h), GluR2-flip (24
h) and GluR2-flop (24
h) isoforms in the RVM after inflammation, whereas the levels of GluR1-flop mRNAs showed no significant change. Western blots demonstrated that the GluR1 protein levels were significantly upregulated at 24
h–3 days (
P<0.05) post-inflammation, compared to that of naive animals. GluR2 protein levels remained unchanged. Immunohistochemistry further demonstrated an increase in GluR1-like immunoreactivity localized to the RVM at 24
h post-inflammation. These findings suggest that AMPA receptors in the RVM undergo selective transcriptional and translational modulation following inflammation and may contribute to activity-dependent plasticity in descending pain modulatory systems after prolonged noxious input.
Summary Objective Osteoarthritis (OA) is a complex and painful disease of the whole joint. At present there are no satisfying agents for treating OA. To promote OA research and improved treatment, ...this review summarizes current preclinical evidence on the development of OA. Methods Preclinical OA research was searched and key findings are summarized and commented. Results Mechanisms of OA-associated pain have been studied in rodent knee OA models produced by intra-knee injection of the chondrocyte glycolytic inhibitor mono-iodoacetate (MIA), surgery, or spontaneous development in some species. These models are clinically relevant in terms of histological damage and functional changes, and are used to study mechanisms underlying mechanical, thermal, ambulatory, body weight supporting-evoked, and ongoing OA pain. Recent peripheral, spinal, and supraspinal biochemical and electrophysiological studies in these models suggest that peripheral pro-inflammatory mediators and neuropeptides sensitize knee nociceptors. Spinal cytokines and neuropeptides promote OA pain, and peripheral and spinal cannabinoids inhibit OA pain respectively through cannabinoid-1 (CB1) and CB1/CB2 receptors. TRPV1 and metalloproteinases contribute and supraspinal descending facilitation of 5-hydroxytryptamine (5-HT)/5-HT 3 receptors may also contribute to OA pain. Conditioned place preference tests demonstrate that OA pain induces aversive behaviors, suggesting the involvement of brain. During OA, brain functional connectivity is enhanced, but at present it is unclear how this change is related to OA pain. Conclusion Animal studies demonstrate that peripheral and central sensitization contributes to OA pain, involving inflammatory cytokines, neuropeptides, and a variety of chemical mediators. Interestingly, brainstem descending facilitation of 5-HT/5-HT3 receptors plays a role OA pain.
Until recently, most clinicians and scientists believed that the experience of pain is perceptually proportional to the amount of incoming peripheral nociceptive drive due to injury or inflammation ...in the area perceived to be painful. However, many cases of chronic pain have defied this logic, leaving clinicians perplexed as to how patients are experiencing pain with no obvious signs of injury in the periphery. Conversely, there are patients who have a peripheral injury and/or inflammation but little or no pain. What makes some individuals experience intense pain with minimal peripheral nociceptive stimulation and others experience minimal pain with serious injury? It is increasingly well accepted in the scientific community that pain can be generated and maintained or, through other mechanisms, suppressed by changes in the central nervous system, creating a complete mismatch between peripheral nociceptive drive and perceived pain. In fact, there is no known chronic pain condition where the observed extent of peripheral damage reproducibly engenders the same level of pain across individuals. Temporomandibular disorders (TMDs) are no exception. This review focuses on the idea that TMD patients range on a continuum—from those whose pain is generated peripherally to those whose pain is centralized (i.e., generated, exacerbated, and/or maintained by central nervous system mechanisms). This article uses other centralized chronic pain conditions as a guide, and it suggests that the mechanistic variability in TMD pain etiology has prevented us from adequately treating many individuals who are diagnosed with the condition. As the field moves forward, it will be imperative to understand each person’s pain from its own mechanistic standpoint, which will enable clinicians to deliver personalized medicine to TMD patients and eventually provide relief in even the most recalcitrant cases.
To study the glutamatergic mechanisms underlying changes in excitability in the brain stem pain modulatory circuitry after injury, we examined GluR1 serine 831 phosphorylation in the rostral ...ventromedial medulla (RVM) after complete Freund’s adjuvant-induced hindpaw inflammation. Western blots indicated a rapid and prolonged (30
min and 7 days post-inflammation) increase in phosphoserine 831 GluR1 protein levels in the RVM. The upregulated GluR1 phosphorylation was blocked by pretreatment, but not by post-treatment, with the local anesthetic, lidocaine, at the site of inflammation. The upregulation of phosphoserine 831 GluR1 was attenuated by pretreatment with chelerythrine, a selective PKC inhibitor, KN-93, a selective CaMKII inhibitor, and two NMDA receptor antagonists, MK-801 and APV. These findings provide new evidence linking in vivo AMPA receptor phosphorylation in the RVM pain modulatory circuitry to the enhanced descending pain modulation after inflammation.
Epigenetic regulation of persistent pain Bai, Guang; Ren, Ke; Dubner, Ronald
Translational research : the journal of laboratory and clinical medicine,
01/2015, Letnik:
165, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs ...gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development or maintenance of persistent pain and possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain.
Neonatal noxious insult produces a long-term effect on pain processing in adults. Rats subjected to carrageenan (CAR) injection in one hindpaw within the sensitive period develop bilateral ...hypoalgesia as adults. In the same rats, inflammation of the hindpaw, which was the site of the neonatal injury, induces a localized enhanced hyperalgesia limited to this paw. To gain an insight into the long-term molecular changes involved in the above-described long-term nociceptive effects of neonatal noxious insult at the spinal level, we performed DNA microarray analysis (using microarrays containing oligo-probes for 205 genes encoding receptors and transporters for glutamate, GABA, and amine neurotransmitters, precursors and receptors for neuropeptides, and neurotrophins, cytokines and their receptors) to compare gene expression profiles in the lumbar spinal dorsal horn (LDH) of adult (P60) male rats that received neonatal CAR treatment within (at postnatal day 3; P3) and outside (at postnatal 12; P12) of the sensitive period. The data were obtained both without inflammation (at baseline) and during complete Freund's adjuvant induced inflammation of the neonatally injured paw. The observed changes were verified by real-time RT-PCR. This study revealed significant basal and inflammation-associated aberrations in the expression of multiple genes in the LDH of adult animals receiving CAR injection at P3 as compared to their expression levels in the LDH of animals receiving either no injections or CAR injection at P12. In particular, at baseline, twelve genes (representing GABA, serotonin, adenosine, neuropeptide Y, cholecystokinin, opioid, tachykinin and interleukin systems) were up-regulated in the bilateral LDH of the former animals. The baseline condition in these animals was also characterized by up-regulation of seven genes (encoding members of GABA, cholecystokinin, histamine, serotonin, and neurotensin systems) in the LDH ipsilateral to the neonatally-injured paw. The largest aberration in gene expression, however, was observed during inflammation of the neonatally injured hindpaws in the ipsilateral LDH, which included thirty-six genes (encoding numerous members of glutamate, serotonin, GABA, calcitonin gene-related peptide, neurotrophin, and interleukin systems). These findings suggest that changes in gene expression may be involved in the long-term nociceptive effects of neonatal noxious insult at the spinal level.
AMITRIPTYLINE reduces pain in patients with painful diabetic neuropathy or other neuropathic pain syndromes,
1
2
3
but treatment is often compromised by the sedation, urinary retention, or ...orthostatic hypotension caused by the drug. It has a wide range of pharmacologic actions, including inhibition of norepinephrine and serotonin reuptake and antagonism of muscarinic cholinergic, histamine H
1
, and alpha-adrenergic receptors.
4
Drugs that selectively affect the neurotransmitter systems responsible for pain relief might be useful substitutes for amitriptyline.
This study was designed to test the hypothesis that amitriptyline relieves neuropathic pain by blocking the reuptake of either norepinephrine or serotonin, neurotransmitters that are . . .
Case-control studies have consistently associated psychological factors with chronic pain in general and with temporomandibular disorder (TMD) specifically. However, only a handful of prospective ...studies have explored whether preexisting psychological characteristics represent risk factors for first-onset TMD. The current findings derive from the prospective cohort study of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 3,263 TMD-free participants completed a battery of psychological instruments assessing general psychological adjustment and personality, affective distress, psychosocial stress, somatic symptoms, and pain coping and catastrophizing. Study participants were then followed prospectively for an average of 2.8 years to ascertain cases of first-onset of TMD, and 2,737 provided follow-up data and were considered in the analyses of TMD onset. In bivariate and demographically adjusted analyses, several psychological variables predicted increased risk of first-onset TMD, including reported somatic symptoms, psychosocial stress, and affective distress. Principal component analysis of 26 psychological scores was used to identify latent constructs, revealing 4 components: stress and negative affectivity, global psychological and somatic symptoms, passive pain coping, and active pain coping. In multivariable analyses, global psychological and somatic symptoms emerged as the most robust risk factor for incident TMD. These findings provide evidence that measures of psychological functioning can predict first onset of TMD. Future analyses in the OPPERA cohort will determine whether these psychological factors interact with other variables to increase risk for TMD onset and persistence.
This article reports that several premorbid psychological variables predict first-onset TMD in the OPPERA study, a large prospective cohort study designed to discover causal determinants of TMD pain. Measures of somatic symptoms were most strongly associated with TMD onset, but perceived stress, previous life events, and negative affect also predicted TMD incidence.
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