ABSTRACT
Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here we examine the role of the SH3 domain of postsynaptic density 95 (PSD95) by using mice that carry a single amino-acid substitution in the polyproline-binding site. Testing multiple forms of plasticity we found sensitization to inflammation was specifically attenuated. The inflammatory response required recruitment of phosphatidylinositol-3-kinase-C2alpha to the SH3-binding site of PSD95. In wild-type mice, wortmannin or peptide competition attenuated the sensitization. These results show that different types of behavioural plasticity are mediated by specific domains of PSD95 and suggest novel therapeutic avenues for reducing inflammatory pain.
Subject(s)
Inflammation/complications , Inflammation/enzymology , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Pain/complications , Pain/enzymology , Phosphatidylinositol 3-Kinases/metabolism , src Homology Domains , Animals , Disks Large Homolog 4 Protein , Guanylate Kinases , Hippocampus/enzymology , Hippocampus/pathology , In Vitro Techniques , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mice , Neuronal Plasticity , Point Mutation/genetics , Protein Binding , Structure-Activity Relationship , Synapses/enzymologyABSTRACT
Nerve impulses are propagated at nodes of Ranvier in the myelinated nerves of vertebrates. Internodal distances have been proposed to affect the velocity of nerve impulse conduction; however, direct evidence is lacking, and the cellular mechanisms that might regulate the length of the myelinated segments are unknown. Ramón y Cajal described longitudinal and transverse bands of cytoplasm or trabeculae in internodal Schwann cells and suggested that they had a nutritive function. Here we show that internodal growth in wild-type nerves is precisely matched to nerve extension, but disruption of the cytoplasmic bands in Periaxin-null mice impairs Schwann cell elongation during nerve growth. By contrast, myelination proceeds normally. The capacity of wild-type and mutant Schwann cells to elongate is cell-autonomous, indicating that passive stretching can account for the lengthening of the internode during limb growth. As predicted on theoretical grounds, decreased internodal distances strikingly decrease conduction velocities and so affect motor function. We propose that microtubule-based transport in the longitudinal bands of Cajal permits internodal Schwann cells to lengthen in response to axonal growth, thus ensuring rapid nerve impulse transmission.
Subject(s)
Nerve Fibers, Myelinated/physiology , Schwann Cells/cytology , Schwann Cells/physiology , Synaptic Transmission/physiology , Animals , Axons/physiology , Behavior, Animal/physiology , Cell Size , Cytoplasm/metabolism , Gene Deletion , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Knockout , Microtubules/metabolism , Muscle, Skeletal/innervation , Myelin Basic Protein/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sciatic Nerve/cytology , Sciatic Nerve/physiologyABSTRACT
BACKGROUND: Chronic established pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. New insights are urgently required, and we reasoned that endogenous processes such as cooling-induced analgesia may point the way to novel strategies for intervention. Molecular receptors for cooling have been identified in sensory nerves, and we demonstrate here how activation of one of these, TRPM8, produces profound, mechanistically novel analgesia in chronic pain states. RESULTS: We show that activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of specific pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, thereby inhibiting the characteristic sensitization of dorsal-horn neurons and behavioral-reflex facilitation. TRPM8 expression was increased in a subset of sensory neurons after nerve injury. The essential role of TRPM8 in suppression of sensitized pain responses was corroborated by specific knockdown of its expression after intrathecal application of an antisense oligonucleotide. We further show that the analgesic effect of TRPM8 activation is centrally mediated and relies on Group II/III metabotropic glutamate receptors (mGluRs), but not opioid receptors. We propose a scheme in which Group II/III mGluRs would respond to glutamate released from TRPM8-containing afferents to exert an inhibitory gate control over nociceptive inputs. CONCLUSIONS: TRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states.
Subject(s)
Analgesia/methods , Cold Temperature , Neuralgia/metabolism , Neuralgia/therapy , TRPM Cation Channels/metabolism , Acrolein/analogs & derivatives , Acrolein/pharmacology , Amino Acids/pharmacology , Analysis of Variance , Animals , Blotting, Western , Dose-Response Relationship, Drug , Electrophysiology , Immunohistochemistry , Male , Menthol/pharmacology , Neuralgia/drug therapy , Oligonucleotides, Antisense , Pyrimidinones/pharmacology , Rats , Rats, Wistar , Receptors, Glutamate/metabolism , Reflex/drug effects , Xanthenes/pharmacologyABSTRACT
BACKGROUND: There is concern that exposure of preterm infants to noxious insults over a prolonged period may have long term effects on their developing nervous system. AIMS: To investigate medium and long term effects of heel pricks in infants over the first year of life. STUDY DESIGN: Study 1-a longitudinal study, 2 days and 4 weeks after heel prick. Study 2-a cross sectional study over the first year of life. SUBJECTS: Study 1-13 healthy preterm (PT) infants. Study 2-63 full term (FT) and 62 PT infants, divided into 3 timed groups (0-20, 21-37 and 38-52 weeks postterm and corrected for prematurity). OUTCOME MEASURES: Threshold responses (flexion withdrawal (FWR) , gross body movements (GBM) and grimace (G)) to increasing mechanical force applied with Von Frey filaments. RESULTS: Study 1-Thresholds were all significantly lower (more sensitive) from the pricked heel compared to the contralateral side at 2 days and 4 weeks. Study 2-There were significant differences in threshold between PT and FT infants at all time points for both FWR (P=0.001, <0.001, <0.001) and GBM (P=<0.001, <0.001, 0.009 respectively), the preterm infants always being lower. The threshold for the FWR in FT infants steadily increased, but the threshold for the PT infants remained the same. GBM thresholds increased during the year in both FT and PT infants, but were always significantly lower in the ex-preterm group (P<0.012). CONCLUSIONS: Either PT birth or repetitive procedures associated with such birth alters the sensitivity threshold of PT infants compared with FT infants for at least the first year of life.
Subject(s)
Infant Behavior , Infant, Premature/psychology , Pain/psychology , Stress, Psychological/psychology , Term Birth/psychology , Cross-Sectional Studies , Heel/injuries , Humans , Infant , Infant, Newborn , Longitudinal Studies , Pain/etiology , Pain Measurement , Pain Threshold , Physical Stimulation/adverse effectsABSTRACT
Chronic pain due to nerve injury is resistant to current analgesics. Animal models of neuropathic pain show neuronal plasticity and behavioral reflex sensitization in the spinal cord that depend on the NMDA receptor. We reveal complexes of NMDA receptors with the multivalent adaptor protein PSD-95 in the dorsal horn of spinal cord and show that PSD-95 plays a key role in neuropathic reflex sensitization. Using mutant mice expressing a truncated form of the PSD-95 molecule, we show their failure to develop the NMDA receptor-dependent hyperalgesia and allodynia seen in the CCI model of neuropathic pain, but normal inflammatory nociceptive behavior following the injection of formalin. In wild-type mice following CCI, CaM kinase II inhibitors attenuate sensitization of behavioral reflexes, elevated constitutive (autophosphorylated) activity of CaM kinase II is detected in spinal cord, and increased amounts of phospho-Thr(286) CaM kinase II coimmunoprecipitate with NMDA receptor NR2A/B subunits. Each of these changes is prevented in PSD-95 mutant mice although CaM kinase II is present and can be activated. Disruption of CaM kinase II docking to the NMDA receptor and activation may be responsible for the lack of neuropathic behavioral reflex sensitization in PSD-95 mutant mice.
Subject(s)
Behavior, Animal , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Hyperalgesia/physiopathology , Nerve Tissue Proteins/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Spinal Cord/physiopathology , Animals , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Disks Large Homolog 4 Protein , Enzyme Activation , Enzyme Inhibitors/pharmacology , Guanylate Kinases , Hyperalgesia/enzymology , Hyperalgesia/metabolism , Intracellular Signaling Peptides and Proteins , Membrane Proteins , Mice , Mice, Mutant Strains , Nerve Tissue Proteins/geneticsABSTRACT
Homologous recombination in ES cells was employed to generate mice with targeted deletion of the first three exons of the gamma-synuclein gene. Complete inactivation of gene expression in null mutant mice was confirmed on the mRNA and protein levels. Null mutant mice are viable, are fertile, and do not display evident phenotypical abnormalities. The effects of gamma-synuclein deficiency on motor and peripheral sensory neurons were studied by various methods in vivo and in vitro. These two types of neurons were selected because they both express high levels of gamma-synuclein from the early stages of mouse embryonic development but later in the development they display different patterns of intracellular compartmentalization of the protein. We found no difference in the number of neurons between wild-type and null mutant animals in several brain stem motor nuclei, in lumbar dorsal root ganglia, and in the trigeminal ganglion. The survival of gamma-synuclein-deficient trigeminal neurons in various culture conditions was not different from that of wild-type neurons. There was no difference in the numbers of myelinated and nonmyelinated fibers in the saphenous nerves of these animals, and sensory reflex thresholds were also intact in gamma-synuclein null mutant mice. Nerve injury led to similar changes in sensory function in wild-type and mutant mice. Taken together, our data suggest that like alpha-synuclein, gamma-synuclein is dispensable for the development and function of the nervous system.
Subject(s)
Nerve Tissue Proteins/deficiency , Neurons/metabolism , Animals , Base Sequence , Cell Compartmentation , Cell Survival , Cells, Cultured , DNA/genetics , Embryonic and Fetal Development , Female , Gene Expression , Gene Targeting , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Neurons/cytology , Motor Neurons/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nervous System/embryology , Nervous System/metabolism , Neurons/cytology , Neurons, Afferent/cytology , Neurons, Afferent/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reflex/physiology , Synucleins , Trauma, Nervous System/physiopathology , alpha-Synuclein , gamma-SynucleinABSTRACT
Over the last two decades there has been a dramatic increase in the literature relating to the mechanisms and management of pain in domestic animals. Understanding the mechanisms of pain is crucial for its effective management. This review highlights the current understanding of the neurophysiology of nociception and the plastic changes involved in chronic pain states. Additionally, we describe a range of novel molecules and pathways that offer opportunities for the development of mechanism-based analgesic therapies. Pain management in animals is limited by pain assessment which remains highly subjective, with clinicians relying on indirect measures of pain, using rating scales and (less frequently) quantifiable physiological and behavioural parameters. The need for a systematic approach which would assess different pain components is well justified. Species-specific issues on pain assessment and management in mammalian companion and farm animals are addressed in the later part of this review.
Subject(s)
Analgesics/therapeutic use , Animals, Domestic , Pain Measurement/veterinary , Pain/veterinary , Animals , Behavior, Animal , Pain/drug therapy , Pain/prevention & control , Pain Measurement/methods , Pain Measurement/standards , Species SpecificityABSTRACT
Chronic pain is sustained by central neuronal sensitization, with many similar characteristics irrespective of the type of injury incurred. Nevertheless, pain arising from nerve injury (neuropathic pain) is resistant to centrally acting analgesics, whereas inflammatory pain responds well. New research indicates that the role of spinal NMDA receptors in chronic pain depends on adaptor proteins of the membrane-associated guanylate kinase (MAGUK) family and raises the possibility that complexes of different composition might contribute differentially to different pain states.
Subject(s)
Nucleoside-Phosphate Kinase/physiology , Pain/etiology , Spinal Cord/metabolism , Animals , Guanylate Kinases , Humans , Receptors, N-Methyl-D-Aspartate/physiologyABSTRACT
PURPOSE: Cancer-induced bone pain (CIBP) affects one third of patients with cancer. Radiotherapy remains the gold-standard treatment; however, laboratory and clinical work suggest that pregabalin may be useful in treating CIBP. The aim of this study was to examine pregabalin in patients with CIBP receiving radiotherapy. PATIENTS AND METHODS: A multicenter, double-blind randomized trial of pregabalin versus placebo was conducted. Eligible patients were age ≥ 18 years, had radiologically proven bone metastases, were scheduled to receive radiotherapy, and had pain scores ≥ 4 of 10 (on 0-to-10 numeric rating scale). Before radiotherapy, baseline assessments were completed, followed by random assignment. Doses of pregabalin and placebo were increased over 4 weeks. The primary end point was treatment response, defined as a reduction of ≥ 2 points in worst pain by week 4, accompanied by a stable or reduced opioid dose, compared with baseline. Secondary end points assessed average pain, interference of pain with activity, breakthrough pain, mood, quality of life, and adverse events. RESULTS: A total of 233 patients were randomly assigned: 117 to placebo and 116 to pregabalin. The most common cancers were prostate (n = 88; 38%), breast (n = 77; 33%), and lung (n = 42; 18%). In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in the placebo arm (adjusted odds ratio, 1.07; 95% CI, 0.63 to 1.81; P = .816). There were no statistically significant differences in average pain, pain interference, or quality of life between arms. There were differences in mood (P = .031) and breakthrough pain duration (P = .037) between arms. Outcomes were compared at 4 weeks. CONCLUSION: Our findings do not support the role of pregabalin in patients with CIBP receiving radiotherapy. The role of pregabalin in CIBP with a clinical neuropathic pain component is unknown.
Subject(s)
Analgesics/therapeutic use , Breakthrough Pain/therapy , Neoplasms/complications , Palliative Care/methods , Pregabalin/therapeutic use , Activities of Daily Living , Adult , Affect , Aged , Analgesics/adverse effects , Analgesics, Opioid/therapeutic use , Bone and Bones , Breakthrough Pain/etiology , Chemoradiotherapy , Double-Blind Method , Female , Humans , Male , Middle Aged , Pain Management/methods , Pain Measurement , Pregabalin/adverse effects , Quality of LifeABSTRACT
Demyelinating diseases can be associated with painful sensory phenomena such as tactile allodynia and hyperalgesia. To study the mechanisms underlying demyelination-induced pain, we have characterized a novel model of demyelination of the sciatic or saphenous nerve. Topical lysolecithin application causes focal demyelination of afferent nerve A-fibers without axonal loss, as assessed either by electron and light microscopy or by immunohistochemical analysis of dorsal root ganglia (DRG) for a neuronal injury marker, activating transcription factor 3. Focal demyelination is accompanied by spontaneous action potentials in afferents and increased expression of neuropeptide Y and Na(v)1.3 sodium channels specifically in DRG neurons that coexpress a specific marker of myelinated afferents. In contrast, expression of tetrodotoxin-resistant, Na(v)1.8 sodium channels is specifically decreased in the same subgroup of DRG cells. Central sensitization of somatosensory processing is also induced, with increased behavioral reflex responsiveness to thermal and mechanical stimuli. These changes are reversed by intrathecal administration of an NMDA receptor antagonist or cannabinoid (CB) receptor agonist, but not by a mu-opioid receptor agonist. Recovery of behavioral reflexes occurred approximately 3 weeks after lysolecithin treatment. This is the first time that demyelination of afferent A-fibers has been shown to specifically induce neuropathic pain and indicates that axonal damage is not a prerequisite for development of the pain state. The profile of phenotypic changes in DRG is distinct from other pain models and displays a sensitivity to NMDA and CB receptor agents that may be exploitable therapeutically.
Subject(s)
Cannabinoids/pharmacology , Demyelinating Diseases/physiopathology , Lysophosphatidylcholines/pharmacology , Mononeuropathies/physiopathology , Peripheral Nerves/physiopathology , Action Potentials/drug effects , Animals , Behavior, Animal/drug effects , Demyelinating Diseases/chemically induced , Demyelinating Diseases/complications , Disease Models, Animal , Drug Administration Routes , Excitatory Amino Acid Antagonists/pharmacology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mononeuropathies/chemically induced , Mononeuropathies/complications , Mononeuropathies/pathology , Nerve Fibers, Myelinated/drug effects , Nerve Fibers, Myelinated/pathology , Neurons, Afferent/drug effects , Neurons, Afferent/pathology , Neurons, Afferent/physiology , Neuropeptide Y/metabolism , Pain/drug therapy , Pain/physiopathology , Peripheral Nerves/drug effects , Peripheral Nerves/pathology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, Opioid, mu/agonists , Reflex/drug effects , Sciatic Nerve/drug effects , Sciatic Nerve/pathology , Sciatic Nerve/physiopathology , Sodium Channels/metabolismABSTRACT
Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.
Subject(s)
Cysteine Endopeptidases/metabolism , Multienzyme Complexes/metabolism , Pain/physiopathology , Sciatic Neuropathy/physiopathology , Ubiquitin/metabolism , Action Potentials/drug effects , Animals , Behavior, Animal , Disease Models, Animal , Electrophysiology , Enzyme Inhibitors/administration & dosage , Hyperalgesia/etiology , Hyperalgesia/physiopathology , In Situ Hybridization , Injections, Spinal , Iontophoresis , Ligation , Male , Multienzyme Complexes/antagonists & inhibitors , Pain/drug therapy , Pain/etiology , Pain Measurement , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiopathology , Proteasome Endopeptidase Complex , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reflex/drug effects , Sciatic Neuropathy/complications , Sciatic Neuropathy/drug therapy , Thiolester Hydrolases/genetics , Thiolester Hydrolases/metabolism , Ubiquitin ThiolesteraseABSTRACT
Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre-emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre-emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre-emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre-treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre-emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre-emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.
Subject(s)
Excitatory Amino Acid Antagonists/administration & dosage , Pain Threshold/drug effects , Pain/prevention & control , Receptors, N-Methyl-D-Aspartate/metabolism , Spinal Cord/drug effects , Analysis of Variance , Animals , Behavior, Animal , Blotting, Western/methods , Disease Models, Animal , Excitatory Amino Acid Antagonists/therapeutic use , Functional Laterality , Gene Expression Regulation/drug effects , Male , Pain/complications , Pain Measurement , Rats , Rats, Wistar , Reaction Time/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Spinal Cord/metabolism , Spinal Cord/pathology , Time Factors , Trauma, Nervous System/complications , Trauma, Nervous System/drug therapyABSTRACT
Reactivation of latent varicella zoster virus (VZV) within sensory trigeminal and dorsal root ganglia (DRG) neurons produces shingles (zoster), often accompanied by a chronic neuropathic pain state, post-herpetic neuralgia (PHN). PHN persists despite latency of the virus within human sensory ganglia and is often unresponsive to current analgesic or antiviral agents. To study the basis of varicella zoster-induced pain, we have utilised a recently developed model of chronic VZV infection in rodents. Immunohistochemical analysis of DRG following VZV infection showed the presence of a viral immediate early gene protein (IE62) co-expressed with markers of A- (neurofilament-200; NF-200) and C- (peripherin) afferent sensory neurons. There was increased expression of neuropeptide Y (NPY) in neurons co-expressing NF-200. In addition, there was an increased expression of alpha2delta1 calcium channel, Na(v)1.3 and Na(v)1.8 sodium channels, the neuropeptide galanin and the nerve injury marker, Activating Transcription Factor-3 (ATF-3) as determined by Western blotting in DRG of VZV-infected rats. VZV infection induced increased behavioral reflex responsiveness to both noxious thermal and mechanical stimuli ipsilateral to injection (lasting up to 10 weeks post-infection) that is mediated by spinal NMDA receptors. These changes were reversed by systemic administration of gabapentin or the sodium channel blockers, mexiletine and lamotrigine, but not by the non-steroidal anti-inflammatory agent, diclofenac. This is the first time that the profile of VZV infection-induced phenotypic changes in DRG has been shown in rodents and reveals that this profile appears to be broadly similar (but not identical) to changes in other neuropathic pain models.
Subject(s)
Amines/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Ganglia, Spinal/virology , Herpesvirus 3, Human/drug effects , Mexiletine/pharmacology , Neuralgia/etiology , Sodium Channels/drug effects , Triazines/pharmacology , Virus Latency/physiology , gamma-Aminobutyric Acid/pharmacology , Amines/therapeutic use , Animals , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Behavior, Animal/drug effects , Behavior, Animal/physiology , Cyclohexanecarboxylic Acids/therapeutic use , Disease Models, Animal , Fluorescent Antibody Technique , Gabapentin , Galanin/metabolism , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Herpes Zoster/metabolism , Herpes Zoster/prevention & control , Herpes Zoster/virology , Herpesvirus 3, Human/physiology , Immediate-Early Proteins/metabolism , Immunohistochemistry , Lamotrigine , Mexiletine/therapeutic use , Neuralgia/prevention & control , Neuralgia, Postherpetic/prevention & control , Neuralgia, Postherpetic/virology , Neurons, Afferent/metabolism , Neuropeptide Y/metabolism , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Reflex/drug effects , Reflex/physiology , Sodium Channels/metabolism , Trans-Activators/metabolism , Triazines/therapeutic use , Viral Envelope Proteins/metabolism , gamma-Aminobutyric Acid/therapeutic useABSTRACT
BACKGROUND AND PURPOSE: An objective measure of pain relief may add important information to patients' self assessment, particularly after a treatment. The study aims were to determine whether measures of physical activity and/or gait can be used in characterizing cancer-induced bone pain (CIBP) and whether these biomarkers are sensitive to treatment response, in patients receiving radiotherapy (XRT) for CIBP. MATERIALS AND METHODS: Patients were assessed before (baseline) and 6-8weeks after XRT (follow up). The following assessments were done: Brief Pain Inventory (BPI), activPAL™ activity meter, and GAITRite® electronic walkway (measure of gait). Wilcoxon, Mann-Whitney and Pearson statistical analyses were done. RESULTS: Sixty patients were assessed at baseline; median worst pain was 7 and walking interference was 5. At follow up 42 patients were assessed. BPI worst pain, average pain, walking interference and total functional interference all improved (p<0.001). An improvement in functional interference correlated with aspects of physical activity (daily hours standing r=0.469, p=0.002) and gait (cadence r=0.341, p=0.03). The activPAL and GAITRite parameters did not change following XRT (p>0.05). In responder analyses there were no differences in activPAL and GAITRite parameters (p>0.05). CONCLUSION: Assessment of physical activity and gait allow a characterization of the functional aspects of CIBP, but not in the evaluation of XRT.
Subject(s)
Bone Neoplasms/radiotherapy , Bone Neoplasms/secondary , Gait/radiation effects , Motor Activity/radiation effects , Pain/physiopathology , Pain/radiotherapy , Aged , Aged, 80 and over , Bone Neoplasms/physiopathology , Female , Humans , Male , Middle Aged , Neoplasms/pathology , Neoplasms/physiopathology , Neoplasms/radiotherapy , Pain/etiology , Pain Measurement , Walking/physiologyABSTRACT
BACKGROUND: Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R. METHODOLOGY AND PRINCIPAL FINDINGS: We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain. CONCLUSIONS: We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.
Subject(s)
Hyperalgesia/immunology , Pain/immunology , Receptor, Melanocortin, Type 1/immunology , Animals , Disease Models, Animal , Female , Humans , Hyperalgesia/genetics , Male , Mice , Mice, Transgenic , Pain/genetics , Receptor, Melanocortin, Type 1/geneticsSubject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Neuralgia/metabolism , Neuronal Plasticity/physiology , Peripheral Nervous System Diseases/metabolism , Receptors, AMPA/metabolism , Animals , Humans , Neuralgia/physiopathology , Peripheral Nervous System Diseases/physiopathology , Posterior Horn Cells/metabolism , Posterior Horn Cells/physiopathology , Presynaptic Terminals/metabolism , Synaptic Transmission/physiologyABSTRACT
Postherpetic neuralgia (PHN), a common complication of herpes zoster, which results from reactivation of varicella zoster virus, is a challenging neuropathic pain syndrome. The incidence and severity of herpes zoster and PHN increases with immune impairment or age and may become a greater burden both in terms of health economics and individual suffering. A clearer understanding of the underlying mechanisms of this disease and translation of preclinical outcomes to the clinic may lead to more efficacious treatment options. Here we give an overview of recent findings from preclinical models and clinical research on PHN.
Subject(s)
Neuralgia, Postherpetic/physiopathology , Animals , Disease Models, Animal , Humans , Neuralgia, Postherpetic/diagnosis , Neuralgia, Postherpetic/drug therapyABSTRACT
BACKGROUND: The newborn infant's response to stimulation with von Frey filaments has previously been examined only at the spinal level as the flexion withdrawal response or abdominal reflex. The threshold for the spinal responses has been shown to be lower following skin damage and visceral pathology. Higher forces of mechanical stimulation elicit other body responses, which are likely to arise from higher levels in the nervous system: these have not been investigated before. OBJECTIVE: To investigate the newborn infants' responses to increasing forces of mechanical (von Frey filament) stimulation and whether their progression is affected by repeated heel prick. SUBJECTS AND METHODS: The study was performed in 31 full term and 77 preterm infants. Graded mechanical forces (using von Frey filaments) were applied to the heels and the abdominal skin. The thresholds for the flexion withdrawal reflex or abdominal reflex and other body responses were recorded. RESULTS: The thresholds for the flexion withdrawal reflex and other body movements to graded mechanical force on the heel were significantly lower in preterm infants compared to full term infants. The threshold for the abdominal reflex and other body responses from graded mechanical stimulation of the abdomen was also significantly lower in preterm infants. In all infants thresholds were further reduced following sensitisation from previous heel pricks. The progression of the responses is independent of gestation or prior sensitisation. CONCLUSION: Both preterm and full term newborn infants respond to graded mechanical stimuli by a series of body responses, which progress in response to increasing force from a simple spinal withdrawal reflex to more complex responses involving higher levels of the central nervous system.
Subject(s)
Heel/innervation , Infant, Newborn/physiology , Infant, Premature/physiology , Motor Activity/physiology , Central Nervous System/embryology , Central Nervous System/physiology , Female , Humans , Male , Physical Stimulation , Reflex, Abdominal/physiologyABSTRACT
Persistent pain has been reported in up to 80% of patients after limb amputation. The mechanisms are not fully understood, but nerve injury during amputation is important, with evidence for the crucial involvement of the spinal N-methyl d-aspartate (NMDA) receptor in central changes. The study objective was to assess the effect of pre-emptively modulating sensory input with epidural ketamine (an NMDA antagonist) on post-amputation pain and sensory processing. The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a randomised epidural infusion (Group K received racemic ketamine and bupivacaine; Group S received saline and bupivacaine). Neither general anaesthesia nor opioids were used during the peri-operative period. Pain characteristics were assessed for 12 months. The primary endpoint was incidence and severity of post-amputation pain. Persistent pain at one year was much less in both groups than in comparable studies, with no significant difference between groups (Group K=21% (3/14) and 50% (7/14); and Group S=33% (5/15) and 40% (6/15) for stump and phantom pain, respectively). Post-operative analgesia was significantly better in Group K, with reduced stump sensitivity. The intrathecal/epidural technique used, with peri-operative sensory attenuation, may have reduced ongoing sensitisation, reducing the overall incidence of persistent pain. The improved short-term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation. Longer term effects on mood were detected in Group K that requires further study.
Subject(s)
Amputation, Surgical , Analgesics/therapeutic use , Ketamine/therapeutic use , Pain, Postoperative/drug therapy , Phantom Limb/drug therapy , Aged , Analgesia, Epidural/methods , Analysis of Variance , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pain Measurement , Phantom Limb/complications , Phantom Limb/psychology , Retrospective Studies , Surveys and Questionnaires , Time FactorsABSTRACT
Laminitis is a common debilitating disease in horses that involves painful disruption of the lamellar dermo-epidermal junction within the hoof. This condition is often refractory to conventional anti-inflammatory analgesia and results in unremitting pain, which in severe cases requires euthanasia. The mechanisms underlying pain in laminitis were investigated using quantification of behavioural pain indicators in conjunction with histological studies of peripheral nerves innervating the hoof. Laminitic horses displayed consistently altered or abnormal behaviours such as increased forelimb lifting and an increased proportion of time spent at the back of the box compared to normal horses. Electron micrographic analysis of the digital nerve of laminitic horses showed peripheral nerve morphology to be abnormal, as well as having reduced numbers of unmyelinated (43.2%) and myelinated fibers (34.6%) compared to normal horses. Sensory nerve cell bodies innervating the hoof, in cervical, C8 dorsal root ganglia (DRG), showed an upregulated expression of the neuronal injury marker, activating transcription factor-3 (ATF3) in both large NF-200-immunopositive neurons and small neurons that were either peripherin- or IB4-positive. A significantly increased expression of neuropeptide Y (NPY) was also observed in myelinated afferent neurons. These changes are similar to those reported in other neuropathic pain states and were not observed in the C4 DRG of laminitic horses, which is not associated with innervation of the forelimb. This study provides novel evidence for a neuropathic component to the chronic pain state associated with equine laminitis, indicating that anti-neuropathic analgesic treatment may well have a role in the management of this condition.