The neuropathic pain is caused by the injury or damage on the sensory nervous system; its pathological manifestations include allodynia, hyperalgesia, and spontaneous pain. About 4–8% of people in our society are suffering from this disease. The maladaptive plasticity refers to the plasticity in the nervous system that leads to a disruption of the function and may be considered as a disease state [1]. Emerging evidences from both human patients and animal models showed that maladaptive plastic changes happened along the sensory pathways, from the peripheral to central nervous system, which may contribute to the generation, development, and maintenance of neuropathic pain. The current special issue focused on the molecular mechanism underlying maladaptive plasticity along sensory pathways; different laboratories around the world investigated the maladaptive change in different signaling pathways at different levels; the contributions in this area will highlight the pain managements in the future.
The transient receptor potential cation channel subfamily V member 1 (TRPV1) is the first identified member of TRPV proteins. TRPV1 can be activated by high temperature or specific chemical stimuli. The activation of TRPV1 in the terminal of nociceptive primary afferents conveys noxious information to the spinal cord and superspinal regions. Recent studies also identified critical roles of TRPV1 in the central regions of pain pathway in pain regulation. In the current issue, T. Jian et al. report that TRPV1 in dorsal root ganglia (DRG) modulates histamine H4 receptor-mediated itch. This finding will extend our understanding of the mechanisms of histamine-induced itch and the interaction of the itch and pain. S.-I. Choi et al. review recent studies on TRPV1-regulated pain, especially pathological pain, and suggest that TRPV1 contributes to pain maintenance. The new data may have revealed novel insights into the roles of spinal cord TRPV1 in regulating spinal plasticity, which may identify a new target for modulating pathological pain.
Low back pain affects a large number of patients. Deformation of DRGs and their nerve roots is implicated in the pathogenesis. W.-J. Han et al. evaluate the analgesic effects of a novel synthesized nitronyl (NIT) nitroxide radicals on radicular low back pain in a rat model generated by chronic DRG compression. The authors report a significant analgesic effect of this agent, probably due to its antioxidation and anti-inflammation effects. Y-.B. Xie et al. describe a new rat animal model of human low back pain, by chronic compression of multiple DRGs on one side of lumber. This rat model develops spontaneous pain, cold allodynia, and hyperalgesia. Activating transcription factor 3 (ATF3) and CGRP are upregulated in bilateral DRG neurons and may contribute to the expression of DRG compression-induced pain.
Matrix metalloproteinases (MMPs) play important roles in nociception and allodynia. Q. Wang et al. report a critical role of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN)/OX47, a key regulator of MMP activities, in neuropathic pain development. Their studies show that SNL leads to OX47 upregulation in ipsilateral DRG and that downregulation of OX47 attenuates SNL-induced mechanical allodynia.
Gate-control theory of pain proposed by Melzack and Wall (1965) explains the regulation of noxious information transmission in the spinal substantia gelatinosa. F. J. R. Pelaez and S. Taniguchi have revisited this theory from the perspective of NMDA receptor-mediated synaptic plasticity and intrinsic plasticity, and the Melzack and Wall circuit was slightly modified by using strictly excitatory nociceptive afferences and was further tested at different pain conditions.
Spinal microglia play critical roles in the developments of chronic pain. A. Jurga et al. report the contribution of TLR2 and TLR4 to neuropathic pain in a chronic constriction injury (CCI) model. They describe a time-dependent upregulation of TLR2, TLR4, MyD88, and TRIF mRNA and protein. In addition, blockade of TLR2 and TLR4 impairs the expression of pain behaviors and opioid analgesia. These findings support TLR2 and TLR4 as putative targets for developing therapeutic approaches.
J. Wang et al. report the involvements of mammalian target of rapamycin (mTOR) in the RVM, a key relay region for the descending pathway, in regulation of neuropathic pain. They show that phosphorylated mTOR protein increases mainly in RVM serotonergic spinally projecting neurons in the spared nerve injury (SNI) model. Infusion of rapamycin decreases both excitatory synaptic transmission and intrinsic excitability of serotonergic neurons, which may underlie the analgesic effects. These findings suggest a novel mechanism by which mTOR inhibitor causes analgesia.
The anterior cingulate cortex (ACC) is a heterogeneous brain region and is involved in regulation of pain, emotion, and sex attraction. Z.-X. Zuo et al. report that nerve ligation leads to AChE upregulation in the ACC. They have tested the analgesic effects of huperzine A, an alkaloid isolated from a Chinese club-moss, on evoked pain and spontaneous pain, and reported a significant analgesic effect on evoked pain but not spontaneous pain, indicating a specific role of AChE in regulation of evoked pain.
We are pleased to introduce this special issue that focuses on the maladaptive plasticity in the pain pathway, in both PNS and CNS. It is becoming clear that pain-related maladaptive changes can occur at a cellular level such as alteration of synaptic transmission and at a molecular level such as the dysregulation of various signaling pathways. The studies collected in this issue will help elucidate the pathogenic mechanism of neuropathic pain and facilitate the development of novel strategies for the pain treatments.
The protective effects of adenovirus-mediated glia cell line-derived neurotrophic factor (GDNF) gene transaction was investigated on cultured motoneurons. First, the dose- and time-response relationship of glutamate neurotoxicity was determined on spinal motoneuron cultures. Then, the effect of the gdnf recombinant adenovirus (AdCMVgdnf) was tested in this cellular model. AdCMVgdnf at 20 MOI (multiplicity of infection) was found to significantly reduce the cell loss of motoneurons, as compared to AdCMVgdnf at 20 MOI, the recombinant adenovirus containing the marker gene lacZ. Furthermore, the adenovirus was proved to mediate erogenous gene expression using X-Gal staining and a semi-quantitative RT-PCR method. These results suggested a therapeutic potential of adenovirus vector-mediated gdnf gene therapy in human motoneuron diseases.
Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats. Co-immunoprecipitation (Co-IP) and fluorescence lifetime-imaging-microscopy-based fluorescence resonance energy transfer (FLIM-FRET) assays showed that MOR heteromerized with CCKBR directly in transfected HEK293 cells. Combined with MOR mutant construction, the third transmembrane domain of MOR (TM3MOR) was demonstrated to participate in heteromerization with CCKBR. Receptor ligand binding, ERK phosphorylation and cAMP assays showed that MOR heteromerization with CCKBR weakened the activity of MOR. A cell-penetrating interfering peptide consisting of TM3MOR and TAT (a transactivator of HIV-1) sequences from the N terminal to the C terminal disrupted the MOR–CCKBR interaction and restored the activity of MOR in transfected HEK293 cells. Furthermore, intrathecal application of the TM3MOR-TAT peptide alleviated CCK-8-injection-induced antagonism to morphine analgesia in rats. These results suggest a new molecular mechanism for CCK-8 antagonism to opioid analgesia in terms of G-protein-coupled receptor (GPCR) interaction through direct heteromerization. Our study may provide a potential strategy for pain management with opioid analgesics. A hormone known to weaken the pain-relieving effects of opioid drugs does so because of interaction between the hormone receptor and the opioid receptor. A team from Peking University in Beijing, China, led by Li Su and You Wan showed that an opioid receptor and a receptor that is activated by a peptide hormone involved in digestion are both found in rat neurons of the spinal cord and spinal ganglion. They demonstrated in human cells that the two receptors could form a single structural complex, and that this process weakened the ability of the opioid receptor to respond to drugs such as morphine. A decoy peptide that disrupted the interaction between the receptors boosted the analgesic effects of morphine in rats. Similar strategies could help with pain management.
It has been established that the mechanisms underlying the analgesic effect induced by electroacupuncture (EA) of low frequency (2～4 Hz) and high frequency (100～200 Hz) are not only quantitatively different but also qualitatively distinct. It has been shown that 2 Hz EA accelerates the release of β endorphin and met enkephalin in CNS, whereas high frequency EA (100 Hz in rats) accelerates the release of Supported by NIDA/INVEST grant (You Wan), National Institute on Drug Abuse, NIH, USA and NIDA grant DA03983 (Jisheng Han), NIH, USA dynorphin in the spinal cord. In the present experiment, we tested this hypothesis in mice lacking beta endorphin. Two pairs of metallic needles were inserted into the acupoints ST 36 and SP6, the needles were fixed in situ and then connected to an electric pulse generator HANS. Electroacupuncture (EA) parameters were as follows: constant current output, rectangular (square) wave pulses with 0.6 ms pulse width in 2 Hz, and 0.2 ms in 100 Hz. Tail flick latency (TFL) evoked by radiant heat was used to serve as the endpoint of pain threshold. The results were as follows: (1) EA of 2 Hz with low intensities (0.3～0.4～0.5 mA in each 10 min steps) showed significantly lower analgesic effect in mice lacking beta endorphin compared to that in wild type mice, whereas 100 Hz low intensity EA stimulation produced analgesia in both β endorphin knock out (KO) mice and wild type mice. (2) EA of 2 Hz at higher intensities (0.8～1.0～1.2 mA) which produced stress reactions induced analgesic effects in knock out as well as in wild type mice. These findings indicated that (1) β endorphin plays an important role in mediating low frequency (2 Hz) EA analgesia, (2) β endorphin is not necessary for mediating high frequency (100 Hz) EA analgesia or stress induced analgesia. These results provide genetic support for the hypothesis that the analgesic effect induced by EA of different frequencies is mediated by different kinds of opioid peptides.
aNeuroscience Research Institute, Peking University, Beijing, China bDepartment of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China cKey Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Beijing, China E-mail address: [email protected] (Y. Wan)
By making a questionnaire among the sophomores in Hubei Vocational - Technical College in November, 2003 , this paper , in view of the actual professional awareness of higher vocational students, concludes some common characteristics, analyzes the causes, and raises some corresponding countermeasures .
Comorbid anxiety and depressive symptoms in chronic pain are a common health problem, but the underlying mechanisms remain unclear. Previously, we have demonstrated that sensitization of the CeA neurons via decreased GABAergic inhibition contributes to anxiety-like behaviors in neuropathic pain rats. In this study, by using male Sprague Dawley rats, we reported that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain. Bilateral electrolytic lesions of CeA, but not lateral/basolateral nucleus of the amygdala (LA/BLA), abrogated both pain hypersensitivity and aversive and depressive symptoms of neuropathic rats induced by spinal nerve ligation (SNL). Moreover, SNL rats showed structural and functional neuroplasticity manifested as reduced dendritic spines on the CeA neurons and enhanced LTD at the LA/BLA-CeA synapse. Disruption of GluA2-containing AMPAR trafficking and endocytosis from synapses using synthetic peptides, either pep2-EVKI or Tat-GluA2(3Y), restored the enhanced LTD at the LA/BLA-CeA synapse, and alleviated the mechanical allodynia and comorbid aversive and depressive symptoms in neuropathic rats, indicating that the endocytosis of GluA2-containing AMPARs from synapses is probably involved in the LTD at the LA/BLA-CeA synapse and the comorbid aversive and depressive symptoms in neuropathic pain in SNL-operated rats. These data provide a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlight that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain. SIGNIFICANCE STATEMENT Several studies have demonstrated the high comorbidity of negative affective disorders in patients with chronic pain. Understanding the affective aspects related to chronic pain may facilitate the development of novel therapies for more effective management. Here, we unravel that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain, and LTD at the amygdaloid LA/BLA-CeA synapse mediated by GluA2-containing AMPAR endocytosis underlies the comorbid aversive and depressive symptoms in neuropathic pain. This study provides a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlights that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.
Electrocortical responses, elicited by laser heat pulses that selectively activate nociceptive free nerve endings, are widely used in many animal and human studies to investigate the cortical processing of nociceptive information. These laser-evoked brain potentials (LEPs) consist of several transient responses that are time-locked to the onset of laser stimuli. However, the functional properties of the LEP responses are still largely unknown, due to the lack of a sampling technique that can simultaneously record neural activities at the surface of the cortex (i.e., electrocorticogram [ECoG] and scalp electroencephalogram [scalp EEG]) and inside the brain (i.e., local field potential [LFP]). To address this issue, we present here an animal protocol using freely moving rats. This protocol is composed of three main procedures: (1) animal preparation and surgical procedures, (2) a simultaneous recording of ECoG and LFP in response to nociceptive laser stimuli, and (3) data analysis and feature extraction. Specifically, with the help of a 3D-printed protective shell, both ECoG and LFP electrodes implanted on the rat's skull were securely held together. During data collection, laser pulses were delivered on the rat's forepaws through gaps in the bottom of the chamber when the animal was in spontaneous stillness. Ongoing white noise was played to avoid the activation of the auditory system by the laser-generated ultrasounds. As a consequence, only nociceptive responses were selectively recorded. Using the standard analytical procedures (e.g., band-pass filtering, epoch extraction, and baseline correction) to extract stimulus-related brain responses, we obtained results showing that LEPs with a high signal-to-noise ratio were simultaneously recorded from ECoG and LFP electrodes. This methodology makes the simultaneous recording of ECoG and LFP activities possible, which provides a bridge of electrocortical signals at the mesoscopic and macroscopic levels, thereby facilitating the investigation of nociceptive information processing in the brain.
Background Multimodal opioid‐sparing analgesia is a key component of an enhanced recovery pathway after surgery that aims to improve postoperative recovery. Transcutaneous electrical acupoint stimulation (TEAS) is assumed to alleviate pain and anxiety and to modify the autonomic nervous system. This study aimed to determine the efficacy of TEAS for sedation and postoperative analgesia in lung cancer patients undergoing thoracoscopic pulmonary resection. Methods A total of 80 patients were randomized into two groups: the TEAS group and the sham TEAS combined with general anesthesia group. Postoperative pain levels at six, 24, 48 hours, and one month after surgery were measured using the visual analogue scale (VAS). Bispectral index (BIS) score during the TEAS prior to anesthetic induction, Observer's Assessment of Alertness/Sedation (OAAS) score, sufentanil consumption during postoperative patient‐controlled intravenous analgesia (PCIA), number of total and effective attempts of PCIA pump use, and incidence of postoperative nausea and vomiting were recorded and analyzed statistically. Results Patients in the TEAS group had significantly lower VAS scores at six, 24, and 48 hours after surgery ( P < 0.01); lower BIS scores at 10, 20, and 30 minutes before induction ( P < 0.01); lower levels of postoperative sufentanil consumption; lower number of PCIA attempts and effective rates ( P < 0.01); lower incidences of nausea at 0, six, 24, and 48 hours; and lower incidence of vomiting at 24 hours after surgery ( P < 0.05). The postoperative OAAS scores were similar between the groups. Conclusions TEAS could be a feasible approach for sedation and postoperative analgesia in thoracoscopic pulmonary resection.
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