Sensory Sensitization Research Articles

MTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK

Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are extensively used as immunosuppressants to prevent transplant rejection and in treatment of certain cancers. In patients, chronic treatment with rapamycin or its analogues (rapalogues) has been reported to lead to sensory hypersensitivity and pain conditions via an unknown mechanism. Here, we show that pharmacological or genetic inhibition of mTORC1 activates the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop. As a result, increased ERK activity induces sensory neuron sensitization, mechanical hypersensitivity, and spontaneous pain. The clinically available adenosine monophosphate-activated protein kinase activator, metformin, which is an antidiabetic drug, prevents rapamycin-induced ERK activation and the development of mechanical hypersensitivity and spontaneous pain. Taken together, our findings demonstrate that activation of the ERK pathway in sensory neurons as a consequence of mTORC1 inhibition leads to the development of pain. Importantly, this effect is abolished by co-treatment with metformin, thus providing a potential treatment option for rapalogue-evoked pain. Our findings highlight the physiological relevance of feedback signaling through mTORC1 inhibition and have important implications for development of pain therapeutics that target the mTOR pathway.

Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients

Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. In 12 healthy controls and 36 patients with neuropathic pain, we assessed clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neuronal calcitonin gene-related peptide staining was quantified. Perception of warm, cold and heat pain and nerve fibre density were reduced in the painful areas compared with the control sites and with healthy controls. Warm and cold detection thresholds correlated best with epidermal innervation density, whereas heat and cold pain thresholds and axon reflex flare correlated best with dermal innervation density. Clinical pain ratings correlated only with epidermal nerve fibre density (r = 0.38, p < 0.05) and better preserved cold detection thresholds (r = 0.39, p < 0.05), but not with other assessed functional and structural parameters. Thermal thresholds, axon reflex measurements and assessment of skin innervation density are valuable tools to characterize and quantify peripheral neuropathy and link neuronal function to different layers of the skin. The severity of small fibre neuropathy, however, did not correspond to clinical pain intensity and a specific parameter or pattern that would predict pain intensity in peripheral neuropathy could not be identified.

Morphine treatment increases polymodal responses of nociceptive fibers in mouse glabrous skin

Patients receiving opioids for pain may experience abnormal pain sensitivity – either hyperalgesia and/or allodynia. We hypothesize that peripheral sensory sensitization contributes to opioid-induced hyperalgesia, and test this using ex vivo mouse glabrous skin-nerve preparations. Adult male C57BL6 mice were injected intraperitoneally with escalating doses of morphine (5, 8, 10, and 15 mg/kg) or saline every 12h for 48h and sacrificed ≈12h following the last injection. Glabrous skin of the hindpaw with plantar nerve attached was dissected free and placed in a recording chamber superfused with artificial interstitial fluid.

Role of Nitric Oxide in Cluster Headache

Nitric oxide (NO) is an important molecule in headache pathophysiology. NO regulates vascular tone and acts as a potent vasodilator, and thus participates in regulating blood flow. NO is also considered to play a role in processing sensory information and pain sensitization. In this article, we review the role of NO in one of the primary headache disorders, cluster headache (CH). The pathophysiology of CH is still not completely understood. A multifactorial genesis where NO is likely to be involved is probable. The level of NO production has been shown to correlate with disease activity in several inflammatory disorders, such as cystitis, multiple sclerosis, and cerebral lupus erythematosus. In this article, the issue of whether similar circumstances apply for CH and also the role of NO in the pathophysiology of CH in a wider perspective are discussed.

Activation of Extracellular Signal-Regulated Protein Kinase 5 is Essential for Cystitis- and Nerve Growth Factor-Induced Calcitonin Gene-Related Peptide Expression in Sensory Neurons

BackgroundCystitis causes considerable neuronal plasticity in the primary afferent pathways. The molecular mechanism and signal transduction underlying cross talk between the inflamed urinary bladder and sensory sensitization has not been investigated.ResultsIn a rat cystitis model induced by cyclophosphamide (CYP) for 48 h, the mRNA and protein levels of the excitatory neurotransmitter calcitonin gene-related peptide (CGRP) are increased in the L6 dorsal root ganglia (DRG) in response to bladder inflammation. Cystitis-induced CGRP expression in L6 DRG is triggered by endogenous nerve growth factor (NGF) because neutralization of NGF with a specific NGF antibody reverses CGRP up-regulation during cystitis. CGRP expression in the L6 DRG neurons is also enhanced by retrograde NGF signaling when NGF is applied to the nerve terminals of the ganglion-nerve two-compartmented preparation. Characterization of the signaling pathways in cystitis- or NGF-induced CGRP expression reveals that the activation (phosphorylation) of extracellular signal-regulated protein kinase (ERK)5 but not Akt is involved. In L6 DRG during cystitis, CGRP is co-localized with phospho-ERK5 but not phospho-Akt. NGF-evoked CGRP up-regulation is also blocked by inhibition of the MEK/ERK pathway with specific MEK inhibitors U0126 and PD98059, but not by inhibition of the PI3K/Akt pathway with inhibitor LY294002. Further examination shows that cystitis-induced cAMP-responsive element binding protein (CREB) activity is expressed in CGRP bladder afferent neurons and is co-localized with phospho-ERK5 but not phospho-Akt. Blockade of NGF action in vivo reduces the number of DRG neurons co-expressing CGRP and phospho-CREB, and reverses cystitis-induced increases in micturition frequency.ConclusionsA specific pathway involving NGF-ERK5-CREB axis plays an essential role in cystitis-induced sensory activation.

Characterization of a reproducible gastric pain model using oral capsaicin titration in healthy volunteers

Sensory sensitization is one of the main pathophysiological hypotheses in functional gastrointestinal disorders (FGIDs). As sensitization may affect various sensory modalities, we aimed to develop a reproducible gastric pain model utilizing polymodal pathways for use in functional and other pain disorders. In this double-blind, cross-over study 42 healthy subjects swallowed one capsule containing either capsaicin 0.5mg or nocebo every 15min until moderate pain (intensity >30 on 100mm visual analogue scale) was attained for at least 5min. Pain was rated every minute. Capsaicin titration was repeated thrice for reliability calculation. Moderate pain in the upper abdomen was successfully achieved in 38 of 42 subjects (90%) with capsaicin titration and in one of 42 (2%) with nocebo. The median dosage required to induce moderate pain for at least 5min was two capsules (interquartile range 1-3) and the median gastric pain intensity was 47 (41-53). The median duration of moderate pain was 8min (5-12). Moderate pain was successfully reproduced with capsaicin in all subjects on study days 2 and 3, with an excellent Cronbach reliability coefficient of >0.8. Standardized gastric pain can be conveniently achieved in a majority of healthy subjects using a simple oral capsaicin titration, with minimal adverse events. The between-test reproducibility is high and nocebo responses are negligible. This technique stimulating a multimodal physiological pathway will be useful in the investigation of sensory changes in FGIDs, including functional dyspepsia.

Role of the transient receptor potential vanilloid 1 in inflammation and sepsis

The transient receptor potential vanilloid 1 (TRPV1) is a thermoreceptor that responds to noxious temperatures, as well as to chemical agonists, such as vanilloids and protons. In addition, its channel activity is notably potentiated by proinflammatory mediators released upon tissue damage. The TRPV1 contribution to sensory neuron sensitization by proalgesic agents has signaled this receptor as a prime target for analgesic and anti-inflammatory drug intervention. However, TRPV1 antagonists have notably failed in clinical and preclinical studies because of their unwanted side effects. Recent reports have unveiled previously unrecognized anti-inflammatory and protective functions of TRPV1 in several diseases. For instance, this channel has been suggested to play an anti-inflammatory role in sepsis. Therefore, the use of potent TRPV1 antagonists as a general strategy to treat inflammation must be cautiously considered, given the deleterious effects that may arise from inhibiting the population of channels that have a protective function. The use of TRPV1 antagonists may be limited to treating those pathologies where enhanced receptor activity contributes to the inflamed state. Alternatively, therapeutic paradigms, such as reduction of inflammatory-mediated increase of receptor expression in the cell surface, may be a better strategy to prevent abrogation of the TRPV1 subpopulation involved in anti-inflammatory and protective processes.

Ret-Dependent and Ret-Independent Mechanisms of Gfl-Induced Sensitization

BackgroundThe GDNF family ligands (GFLs) are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP) from isolated mouse DRG.ResultsInhibitors of the mitogen-activated protein kinase (MAPK) pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K) pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons.ConclusionsThese data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.

Abnormal cortical responses to somatosensory stimulation in medication-overuse headache

BackgroundMedication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA.MethodsWe recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks.ResultsIn episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification.Conclusions In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission.

Use of Temporary Implantable Biomaterials to Reduce Leg Pain and Back Pain in Patients with Sciatica and Lumbar Disc Herniation

The principle etiology of leg pain (sciatica) from lumbar disc herniation is mechanical compression of the nerve root. Sciatica is reduced by decompression of the herniated disc, i.e., removing mechanical compression of the nerve root. Decompression surgery typically reduces sciatica more than lumbar back pain (LBP). Decompression surgery reduces mechanical compression of the nerve root. However, decompression surgery does not directly reduce sensitization of the sensory nerves in the epidural space and disc. In addition, sensory nerves in the annulus fibrosus and epidural space are not protected from topical interaction with pain mediators induced by decompression surgery. The secondary etiology of sciatica from lumbar disc herniation is sensitization of the nerve root. Sensitization of the nerve root results from a) mechanical compression, b) exposure to cellular pain mediators, and/or c) exposure to biochemical pain mediators. Although decompression surgery reduces nerve root compression, sensory nerve sensitization often persists. These observations are consistent with continued exposure of tissue in the epidural space, including the nerve root, to increased cellular and biochemical pain mediators following surgery. A potential contributor to lumbar back pain (LBP) is stimulation of sensory nerves in the annulus fibrosus by a) cellular pain mediators and/or b) biochemical pain mediators that accompany annular tears or disruption. Sensory fibers located in the outer one-third of the annulus fibrosus increase in number and depth as a result of disc herniation. The nucleus pulposus is comprised of material that can produce an autoimmune stimulation of the sensory nerves located in the annulus and epidural space leading to LBP. The sensory nerves of the annulus fibrosus and epidural space may be sensitized by topical exposure to cellular and biochemical pain mediators induced by lumbar surgery. Annulotomy or annular rupture allows the nucleus pulposus topical access to sensory nerve fibers, thereby leading to LBP. Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators.

An update on pain physiology: the relevance of Craig's and Jänig's hypotheses for hypnotic analgesia

AbstractThe aim of the present review is to discuss two interesting hypotheses that explain the pathophysiology of pain: (1) Arthur Craig's hypothesis that the experience of pain, elicited by specific sensors projecting into the central nervous system through afferent pathways, is relevant for homeostasis and represents a specific emotion related to a homeostatic behavioural drive; and (2) Wilfrid Jänig's hypothesis that, in functional chronic pain syndromes, specific changes occur in autonomic, endocrine and somatic motor systems interactions which, then, result in dysregulation involving peripheral, spinal and brain mechanisms. Theoretically, on the basis of these two hypotheses, hypnotic suggestions for analgesia can affect pain at multiple levels, including its generation at the periphery, secondary sensory neurons sensitization, and modulation of endocrine/immune responses through the modulation of autonomic activity. Copyright © 2009 British Society of Experimental &amp; Clinical Hypnosis. Published by John Wiley &amp; Sons, Ltd.

Fibronectin stimulates TRPV1 translocation in primary sensory neurons

Extracellular matrix (ECM) molecules are highly variable in their composition and receptor recognition. Their ubiquitous expression profile has been linked to roles in cell growth, differentiation, and survival. Recent work has identified certain ECM molecules that serve as dynamic signal modulators, versus the more-recognized role of chronic modulation of signal transduction. In this study, we investigated the role that fibronectin (FN) plays in the dynamic modulation of transient receptor potential family V type 1 receptor (TRPV1) translocation to the plasma membrane in trigeminal ganglia (TG) sensory neurons. Confocal immunofluorescence analyses identify co-expression of the TRPV1 receptor with integrin subunits that bind FN. TG neurons cultured upon or treated with FN experienced a leftward shift in the EC(50) of capsaicin-stimulated neuropeptide release. This FN-induced increase in TRPV1 sensitivity to activation is coupled by an increase in plasma membrane expression of TRPV1, as well as an increase in tyrosine phosphorylation of TRPV1 in TG neurons. Furthermore, TG neurons cultured on FN demonstrated an increase in capsaicin-mediated Ca(2+) accumulation relative to neurons cultured on poly-D-lysine. Data presented from these studies indicate that FN stimulates tyrosine-phosphorylation-dependent translocation of the TRPV1 receptor to the plasma membrane, identifying FN as a critical component of the ECM capable of sensory neuron sensitization.

Synaptically Evoked Glutamate Transporter Currents in Spinal Dorsal Horn Astrocytes

BackgroundRemoving and sequestering synaptically released glutamate from the extracellular space is carried out by specific plasma membrane transporters that are primarily located in astrocytes. Glial glutamate transporter function can be monitored by recording the currents that are produced by co-transportation of Na+ ions with the uptake of glutamate. The goal of this study was to characterize glutamate transporter function in astrocytes of the spinal cord dorsal horn in real time by recording synaptically evoked glutamate transporter currents.ResultsWhole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG) area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz) repetitive stimulation.ConclusionThese results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.

Migrainous Corpalgia: Body Pain and Allodynia Associated with Migraine Attacks

Cephalic and extracephalic allodynia are recognized as a common sign of sensory sensitization during migraine episodes. However, the occurrence of body pain in migraine has not been thoroughly explored. Here we report three patients presenting with spontaneous body pain in association with migraine attacks. A 41-year-old woman experienced face and limb pain along with migraine headaches; it started before, during or after headache, was usually ipsilateral to head pain, and could last from minutes to days. A 39-year-old woman had pain in her right limbs, back and neck for 30-60 min prior to right-sided migraine headaches. A 30-year-old woman perceived pain in her left upper limb for 24-48 h prior to left-sided migraine headaches. All patients had allodynia to mechanical stimuli over the painful areas. Spontaneous body pain may be associated with migraine attacks. Together with allodynia, this might be a consequence of central sensitization.

Contribution by DRt descending facilitatory pathways to maintenance of spinal neuron sensitization in rats

We investigated in different experimental rat models the potential facilitatory contribution of the medullary dorsal reticular nucleus (DRt) descending pathway to the expressions of the sensory spinal neuron sensitization such as increased spontaneous and noxious evoked activities, responsivity to heterotopic afferences stimulation and long lasting afterdischarges (ADs). We carried out experiments by recording from ipsilateral lumbar Wide Dynamic Range (WDR) neurons and by simultaneously monitoring the DRt neuron activity in neuropathic pain rats with chronic constriction injury of one sciatic nerve (CCI), in sham-operated and in “intact” rats. In particular, we recorded the spinal neuron spontaneous activities and the activities evoked by noxious stimulations of ipsi- and contralateral sciatic supplied areas before and during DRt activity blockade. Additionally, in “intact rats” we modulated WDR activity by iontophoretic NMDA to mimic CCI WDR hyperactivity without peripheral damage. We found that during DRt activity blockade in CCI rat neurons and in “intact” rat NMDA-treated neurons, the spontaneous activity was significantly reduced, the responses to contralateral sciatic area stimulation were reduced or suppressed, the responses to ipsilateral sciatic area were poorly affected (slightly reduced or unaffected), except for the poststimulus afterdischarges that were mostly suppressed. In sham-operated rats, the neuronal activity was not affected by DRt blockade. The finding that during the DRt nucleus blockade some expressions of spinal neurons sensitization, seemingly associated to sensory disorders in neuropathic pain, fade or extinguish designates a likely facilitatory role of DRt in the maintenance of neuronal sensitization and thus a contribution to neuropathic pain state.

Perioperative pain

Incisional pain remains underevaluated and undermanaged while evidence is growing that perioperative treatments strongly influence patients' outcome. The present review examines the recent developments in mechanisms underlying perioperative pain and questions current understanding of incisional pain features observed in patients. Experimental models of incisional pain have highlighted specific mechanisms underlying perioperative pain plasticity, i.e. sensitization of sensory processing, clinically expressed by the development of hyperalgesia. In patients, however, the long-term impact of sensory system sensitization, e.g. development of residual pain, as well as the effects of perioperative pain management on sensitization, are still poorly understood, partly because most of the trials assess only the subjective experience of pain (by evaluation of either pain intensity or analgesic needs) instead of directly measuring objective changes (i.e. hyperalgesia) with quantitative sensory testing. Experimental studies and recent clinical trials using objective measures of sensory processing sensitization induced by surgical incision have shown the importance of hyperalgesia in perioperative pain. Effective perioperative block of nociceptive inputs from the wound as well as use of antihyperalgesic and analgesic drugs in combination seem the best way to control postoperative pain and specifically to prevent central sensitization.

Rat Basophilic Leukemia Cells (RBL-2H3) Generate Prostaglandin D2 (PGD2) after Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES) activation

Increasing evidence indicates that local neurogenic inflammation, possibly in response to different stimuli, may be involved in sensory nerve sensitization, migraine generation and some other precipitating events leading to neuronal dysfunction in the brain. In addition, mast cells generate eicosanoids that are linked to asthma and other inflammatory diseases. Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a small protein and a prototype member of the CC chemokine-beta subfamily with chemoattractant and inflammatory properties. In this study we used the RBL-2H3 cell line to determine whether or not these cells generate prostaglandin D2 (PGD2) after treatment with RANTES. After 4 hours of incubation, RBL-2H3 cells cultured with RANTES at 20 ng/mL released large amounts of PGD2 in a dose-response manner compared to control. Moreover, RBL-treated RANTES generated a large quantity of histamine. Our study confirms once again the proinflammatory action of RANTES, in this case acting on the stimulation of the arachidonic acid cascade product PGD2.

Rat basophilic leukemia cells (RBL-2H3) generate prostaglandin D2 (PGD2) after regulated upon activation, normal T-cell expressed and secreted (RANTES) activation

Increasing evidence indicates that local neurogenic inflammation, possibly in response to different stimuli, may be involved in sensory nerve sensitization, migraine generation and some other precipitating events leading to neuronal dysfunction in the brain. In addition, mast cells generate eicosanoids that are linked to asthma and other inflammatory diseases. Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a small protein and a prototype member of the CC chemokine-beta subfamily with chemoattractant and inflammatory properties. In this study we used the RBL-2H3 cell line to determine whether or not these cells generate prostaglandin D2 (PGD2) after treatment with RANTES. After 4 hours of incubation, RBL-2H3 cells cultured with RANTES at 20 ng/mL released large amounts of PGD2 in a dose-response manner compared to control. Moreover, RBL-treated RANTES generated a large quantity of histamine. Our study confirms once again the proinflammatory action of RANTES, in this case acting on the stimulation of the arachidonic acid cascade product PGD2.

Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene

Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21 ras. Loss of NF1 results in an increase in activity of the p21 ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21 ras transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) ( Nf1+/−). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/− mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/− mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5–7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/− neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/− neurons was more pronounced than in Nf1+/− sensory neurons that were treated with nerve growth factor continuously for 5–7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

Molecular mechanisms of antimigraine drugs: past, present, and future

Pharmacotherapeutic treatments for migraine have been documented for more than a century. Drugs that are effective in aborting an ongoing migraine attack exhibit a diversity of molecular mechanisms of action, but usually produce constriction of cranial arterial blood vessels, reversal of neurogenic inflammatory processes, and/or inhibition of sensory neuronal firing. This general understanding of drug action has led to the development of a unitary hypothesis for migraine pathophysiology, in which the onset of migraine is associated with activation of the trigemino-vascular system. Drugs which inhibit or reverse the activation of this system are effective acute treatments for migraine. Drugs useful in migraine prophylaxis have been discovered largely serendipitously, and display a fundamentally different pharmacology to the acutely effective agents. These drugs act at membrane receptors and ion channels, or by targeting intracellular biochemical pathways, and tend to reduce neuronal excitability in higher centers of the CNS. However, other than to suggest that this inhibits various migraine trigger events, it is not yet possible to delineate precisely how these drugs act to decrease the frequency and severity of migraine attacks. More recently, it has been observed that migraine is accompanied by sensory neuronal central sensitization that manifests as cutaneous allodynia in territory innervated by the trigeminal nerve. Although little is presently known about the ability of prophylactic drugs to modulate this process, it was recently shown that acute relief of migraine with triptan drugs is only reliably achieved when the drugs are given prior to the development of central sensitization. This important observation suggests that inhibition of migraine-related central sensitization could be an important new focus for future drug discovery, and may, for the first time, provide a rational target for the development of preventative medicines.