Modulation Of Nociceptive Signals Research Articles

Modulatory Processes in Craniofacial Pain States.

Pain is a common symptom associated with many disorders affecting the craniofacial tissues that include the teeth and their supporting structures, the jaw, face and tongue muscles, and the temporomandibular joint. Most acute craniofacial pain states are easily recognized and readily treated, but chronic craniofacial pain states (e.g., temporomandibular disorders [TMD], trigeminal neuropathies, and some headaches) may be especially challenging to manage successfully. This chapter provides an overview of the processes that underlie craniofacial pain, with a focus on the pain-modulatory mechanisms operating in craniofacial tissues and in the central nervous system (CNS), including the role of endogenous chemical processes such as those involving opioids. The chapter outlines in particular findings from preclinical studies that have provided substantial information about the neural as well as nonneural (e.g., glial) processes involved in the initiation, transmission, and modulation of nociceptive signals in the trigeminal system, and also draws attention to their clinical correlates. The increased understanding gained from these preclinical studies of how nociceptive signals can be modulated will contribute to improvements in presently available therapeutic approaches to manage craniofacial pain as well as to the development of novel analgesic approaches.

Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions.

Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 (CB1) are essential in the modulation of nociceptive signaling in the spinal cord dorsal horn that underlies different pathological pain states. TRPV1 and CB1 receptors share the endogenous agonist anandamide (AEA), produced from N-arachidonoylphosphatidylethanolamine (20:4-NAPE). We investigated the effect of the anandamide precursor 20:4-NAPE on synaptic activity in naive and inflammatory conditions. Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) from superficial dorsal horn neurons in rat acute spinal cord slices were used. Peripheral inflammation was induced by subcutaneous injection of carrageenan. Under naive conditions, mEPSCs frequency (0.96 ± 0.11 Hz) was significantly decreased after 20 μM 20:4-NAPE application (55.3 ± 7.4%). This 20:4-NAPE-induced inhibition was blocked by anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. In addition, the inhibition was prevented by the CB1 receptor antagonist PF 514273 (0.2 μM) but not by the TRPV1 receptor antagonist SB 366791 (10 μM). Under inflammatory conditions, 20:4-NAPE (20 μM) also exhibited a significant inhibitory effect (74.5 ± 8.9%) on the mEPSCs frequency that was prevented by the TRPV1 receptor antagonist SB 366791 but not by PF 514273 application. Our results show that 20:4-NAPE application has a significant modulatory effect on spinal cord nociceptive signaling that is mediated by both TRPV1 and CB1 presynaptic receptors, whereas peripheral inflammation changes the underlying mechanism. The switch between TRPV1 and CB1 receptor activation by the AEA precursor 20:4-NAPE during inflammation may play an important role in nociceptive processing, hence the development of pathological pain.

Salivary CGRP can monitor the different migraine phases: CGRP (in)dependent attacks.

CGRP plays a key role in the transmission and modulation of nociceptive signals and is a critical component in the pathogenesis of migraine. To assess saliva as a substrate to measure CGRP by comparing interictal levels in patients with episodic migraine and controls; and to evaluate CGRP's temporal profile during migraine attacks. This prospective observational pilot study included young women with episodic migraine and healthy controls. We monitored salivary CGRP-like immunoreactivity (CGRP-LI) during 30 consecutive days and during migraine attacks. We considered six timepoints for the analysis: interictal (72h headache free), preictal (PRE-24h before the attack), ictal (headache onset, after 2h, after 8h), postictal (POST-24h after the attack). CGRP levels were quantified by ELISA. 44 women (22 with episodic migraine, 22 healthy controls) were recruited. Differences in interictal salivary levels of CGRP between patients and controls (Me [IQR]: 98.0 [80.3] (95% CI 56.6, 124.0) vs. 54.3 [44.0] (95% CI 42.2, 70.1) pg/mL, p = 0.034) were found. An increase in CGRP levels during migraine attacks was detected (pre:169.0 [95% CI 104.2-234.0]; headache onset: 247.0 [181.9-312.0]; after 2h: 143.0 [77.6-208.0]; after 8h: 169.0 [103.5-234.0], post: 173.0 [107.8-238.0]). Patients were classified as having CGRP-dependent (79.6%) and non-CGRP dependent migraine attacks (20.4%) according to the magnitude of change between preictal and ictal phase. Accompanying symptoms such as photophobia and phonophobia were significantly associated to the first group. Salivary CGRP-LI levels, which interictally are elevated in episodic migraine patients, usually increase during a migraine attack in the majority of patients. However, not every attack is CGRP-dependent, which in turn, might explain different underlying pathophysiology and response to treatment.

Conditioned Pain Modulation Decreases Over Time in Patients With Neuropathic Pain Following a Spinal Cord Injury

Background Neuropathic pain is a major problem following spinal cord injury (SCI). Central mechanisms involved in the modulation of nociceptive signals have been shown to be altered at the chronic stage, and it has been hypothesized that they might play a role in the development of chronic pain. Objective This prospective longitudinal study aimed to describe the evolution of pain modulation mechanisms over time after SCI, and to explore the relationships with the presence of clinical (neuropathic and musculoskeletal) pain. Methods Patients with an SCI were assessed on admission (n = 35; average of 38 days postinjury) and discharge (n = 25; average of 131 days postinjury) using the International Spinal Cord Injury Pain Basic Data Set. Conditioned pain modulation was assessed using the cold pressor test (10 °C; 120 s) as the conditioning stimulus and tonic heat pain, applied above the level of injury, as the test stimulus (120 s). Heat pain threshold was also assessed. Results A marked decrease in the efficacy of conditioned pain modulation was observed over time, with 30.2% of inhibition at admission and only 12.9% at discharge on average (P = .010). This decrease was observed only in patients already suffering from neuropathic pain at admission and was not explained by a general increase in sensitivity to thermal nociceptive stimuli. Conclusion These results suggest that the presence of neuropathic pain leads to a decrease in conditioned pain modulation over time, rather than supporting the hypothesis that inefficient conditioned pain modulation mechanisms are leading to the development of neuropathic pain.

Src activation in the hypothalamic arcuate nucleus may play an important role in pain hypersensitivity

Src family of kinases (SFKs) has been found to play an important role in the regulation of nociception. However, how each member of this family acts in the central nervous system (CNS) structures involved in the relay and/or modulation of nociceptive signals, and thereby contributes to the formation and maintenance of pain hypersensitivity, is still a challenge. In this work, a combined study using biochemical, genetic and behavioral approaches was conducted. We found that the expression of activated SFKs in the hypothalamic arcuate nucleus (ARC) area was significantly increased following the development of inflammation induced by injection of complete freund’s adjuvant (CFA) into the hind paw of rats. Furthermore, we identified that Src, but not Fyn or Lyn in the Src family, was activated, and that Src knockdown in the ARC area blocked the inflammation-induced increases in the expression of activated SFKs, the N-Methyl-D-aspartate receptor (NMDAR) GluN2B subunit and phosphorylated GluN2B at Y1472 in this region. Moreover, the CFA injection-induced allodynia and hyperalgesia, and the analgesic effect produced by systemic application of the SFK inhibitor, SU6656, were significantly diminished. However, the Src knockdown did not induce any change in the expression of activated SFKs and the NMDAR GluN2B subunit in normal rats which were not injected with CFA. Neither the Src knockdown nor the systemic application of SU6656 affected the mechanical and thermal sensitivity of the normal rats. Thus, Src activation in the ARC may be a key event for formation and maintenance of pain hypersensitivity associated with peripheral inflammation.

Mechanisms of craniofacial pain.

Aim To provide an overview of mechanisms underlying craniofacial pain; to highlight peripheral and central adaptations that may promote chronification of pain in craniofacial pain states such as migraine and temporomandibular disorders (TMD). Background Pain is a common symptom associated with disorders involving craniofacial tissues including the teeth and their supporting structures, the temporomandibular joint and the muscles of the head. Most acute painful craniofacial conditions are easily recognized and well managed, but others, especially those that are chronic (e.g., migraine, TMD and trigeminal neuropathies), present clinical challenges. Preclinical studies have provided substantial information about the anatomical and physiological mechanisms related to the initiation and modulation of nociceptive signals in the trigeminal system. While knowledge of the mechanisms underlying chronic craniofacial pain remains limited, both clinical and preclinical investigations suggest that changes in afferent inputs to the brain as well as in brain structure and modulatory pathways occur in chronic pain. Collectively, these changes result in amplification of nociception that promotes and sustains craniofacial chronic pain states. Conclusions The increased understanding gained of the physiological and pathological processing of nociception in the trigeminal system has provided new perspectives for the mechanistic understanding of acute craniofacial pain conditions and the peripheral and central adaptations that are related to pain chronification. Such knowledge may contribute to improvements in currently available treatments as well as to the development of novel analgesic therapies.

The Role of The TRPV1 Endogenous AgonistN-Oleoyldopamine in Modulation of Nociceptive Signaling at the Spinal Cord Level

Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 microM) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 microM) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34 degrees C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.

Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP

It has been suggested that spinal cord long-term potentiation (LTP) may contribute to hypersensitivity and hyperalgesia. We have investigated if noxious stimulus-induced spinal cord LTP might have a long lasting effect on supraspinal neuronal activity. First, we verified that spinal LTP was induced by electrical high frequency stimuli (HFS) conditioning applied to the sciatic nerve. The C-fibre response in the dorsal horn reached a twofold increase 150 min after HFS ( t-test, p < 0.01, n = 6). Then, to study the metabolic supraspinal activity following the same stimulation protocol, we used small animal positron emission tomography (PET) and the glucose analog [ 18F]-fluorodeoxyglucose (FDG). With this combined approach we measured changes in regional supraspinal activity at two time points in HFS conditioned and in sham animals; acute (immediately after HFS/sham, n = 4) and late phase (150 min after HFS/sham, n = 10). Comparisons between HFS and sham groups revealed that induction of spinal LTP was followed by an acute metabolic response in the primary somatosensory cortex (S1), but also various slower metabolic adaptations in brain regions involved in modulation of nociceptive signaling and descending inhibition, i.e., amygdala, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT) ( t-test, p < 0.05). The study demonstrates that PET may be used as an in vivo method to study regional brain metabolic activity between different conditions. It is concluded that noxious sciatic stimuli which induce spinal cord LTP also affect supraspinal metabolic activity. We suggest that these changes might illustrate a supraspinal maladaptive dysfunction involved in pain hypersensitivity and hyperalgesia.

Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes

Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (ORL1 receptor), has been demonstrated to play an important role in modulation of nociceptive signals. In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freund’s adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro. The results showed: (1) CFA-induced peripheral inflammation evoked robust astrocyte activation and proinflammatory cytokines spinally; (2) down-regulation of cytokine mRNA transcripts by intrathecal administration of N/OFQ, the effects produced by N/OFQ were abolished by combination with ORL1 receptor-specific antagonist [Nphe 1]N/OFQ(1–13)NH 2; (3) ORL1 receptor was expressed on astrocytes of rat spinal cord; (4) cytokine gene expression was inhibited in astrocyte cultures exposed to N/OFQ, the inhibiting effects of N/OFQ were significantly blocked by [Nphe 1]N/OFQ(1–13)NH 2. The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway.

Down-regulation of GFRα-1 expression by antisense oligodeoxynucleotide aggravates thermal hyperalgesia in a rat model of neuropathic pain

Glial cell line-derived neurotrophic factor (GDNF) has been hypothesized to play an important role in the modulation of nociceptive signals especially during neuropathic pain. The present study examined the expression of GDNF and GFRα-1 (the high-affinity receptor of GDNF) in dorsal root ganglions (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. In order to address the role of GDNF and GFRα-1 in neuropathic pain, antisense oligodeoxynucleotide (ODN) specifically against GFRα-1 was intrathecally administered to result in down-regulation of GFRα-1 expression. The results showed that both the protein and mRNA levels of GDNF and GFRα-1 were significantly increased after CCI, while the thermal hyperalgesia of neuropathic pain rats could be significantly aggravated by antisense ODN treatment, but not by normal saline (NS) or mismatch ODN treatment. The present study demonstrated that endogenous GDNF and GFRα-1 might play an anti-hyperalgesic role in neuropathic pain of rats. In addition, we found a down-regulation of somatostatin (SOM) in DRG and spinal dorsal horn after expression of GFRα-1 was knocked down, which suggested the possible relationship between the anti-hyperalgesic effect of GDNF and GFRα-1 on neuropathic pain and endogenous SOM.

Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during electroacupuncture treatment in neuropathic pain rats

Injury to the nervous system occasionally leads to intense and persistent neuropathic pain, which is resistant to conventional analgesic methods. It was reported that electroacupuncture (EA) had potent analgesic effect on neuropathic pain by activating various endogenous transmitters such as the opioid peptides. Glial cell line-derived neurotrophic factor (GDNF) has been hypothesized to play an important role in modulation of nociceptive signals especially during neuropathic pain state. Using immunohistochemistry, Western blot, and RT-PCR analysis techniques, the present study observed the effects of EA on the expression of GDNF and GDNF family receptor α-1 (GFRα-1, the high-affinity receptor of GDNF) in neuropathic pain rats. The results showed that both protein and mRNA levels of GDNF and GFRα-1 in the dorsal root ganglions (DRG), as well as GDNF protein in the spinal dorsal horn, were significantly increased after chronic constriction injury (CCI) of the rats’ sciatic nerve and could be further enhanced by EA treatment. The present data demonstrated that EA could activate endogenous GDNF and GFRα-1 system of neuropathic pain rats and this might underlie the effectiveness of EA in the treatment of neuropathic pain.

Recent Insights into Brainstem Mechanisms Underlying Craniofacial Pain

This article briefly highlights some of the recent advances in knowledge of the neural processes underlying pain in the face and mouth. It particularly focuses on those mechanisms operating in the brainstem that are involved in the transmission and modulation of nociceptive signals and that reveal a remarkable degree of plasticity following injury or inflammation of craniofacial tissues. Insights into these processes hold promise of the development of new or improved therapeutic procedures for the relief of pain.

S2-5 Intracellular modulation of nociceptive signals in the rat Dorsal commissural neurons by noradrenaline and serotonin

S2-5 Intracellular modulation of nociceptive signals in the rat Dorsal commissural neurons by noradrenaline and serotonin

S2-5 Intracellular modulation of nociceptive signals in the rat dorsal commissural neurons by noradrenaline and serotonin

S2-5 Intracellular modulation of nociceptive signals in the rat dorsal commissural neurons by noradrenaline and serotonin

Role of opioid receptors in the spinal antinociceptive effects of neuropeptide FF analogues.

1. Neuropeptide FF (NPFF) has been shown to produce antinociceptive effects and enhance morphine-induced antinociception after intrathecal (i.t.) injection. In this study, the spinal effects of two NPFF analogues, -D-Tyr1,(NMe)Phe3-NPFF (1DMe) and [D-Tyr1,D-Leu2,D-Phe3]NPFF (3D), which are resistant to degradation and exhibit a high affinity for NPFF binding sites, were examined in tests of thermal and mechanical nociception. 2. 1DMe and 3D produced potent dose-dependent spinal antinociception in the tail-flick test. On a molar basis, 1DMe was 20 and 50 times more potent than 3D and morphine, respectively, and high doses of 1DMe and 3D produced a sustained antinociceptive effect without visible signs of motor impairment. 3. Spinal antinociceptive effects produced by 1DMe (0.86 nmol) or 3D (8.6 nmol) were significantly reduced by i.t. co-administration of naloxone (11 nmol) or i.t. pre-administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 9.25 nmol) or beta-funaltrexamine (beta-FNA, 2 nmol) or naltrindole (2.2 nmol). The doses of the mu-antagonists (CTOP and beta-FNA) or the delta-antagonist (naltrindole) used in 1DMe and 3D experiments blocked the antinociceptive effects of mu- or delta-receptor-selective agonists. 4. When administered in combination with antinociceptive doses of the mu-receptor agonist, morphine (13.2 nmol) or the delta-receptor agonist, [D-Ala2]deltorphin I (20 nmol), sub-effective dose of 1DMe or 3D (0.009 nmol) enhanced and prolonged the spinal effects of these opioid agonists. 5. The results of this study show that spinal mu- and delta-opioid receptors play a role in antinociception produced by NPFF analogues. These results also suggest a role for NPFF in modulation of nociceptive signals at the spinal level.