Involvement Of Sensory Neurons Research Articles

Pathophysiology of Prurigo Nodularis: Neuroimmune Dysregulation and the Role of Type 2 Inflammation.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized by multiple, intensely pruritic, distinctive nodular lesions. Subsequent scratching can further intensify the pruritus, culminating in a self-reinforcing itch-scratch cycle, which drives lesion development. The latest data indicate dysregulation of the neuroimmune axis in PN pathogenesis, including the involvement of sensory neurons, key effector immune cells, proinflammatory cytokines, dermal fibroblasts, and pruritogens. In this review, we highlight evidence supporting the role of type 2 immune axis dysregulation in driving the clinical presentation of PN and discuss how related signaling pathways may offer effective therapeutic targets to control PN signs and symptoms.

A Case Report of Sensory Guillain-Barré Syndrome with Prominent Autonomic Dysfunction in a Systemic Lupus Erythematosus Patient

Sensory Guillain-Barré syndrome (GBS) is a rare heterogeneous subgroup of GBS characterized by the primary involvement of sensory neurons resulting in a distinctive clinical presentation. Sensory GBS usually occurs with acute and monophasic sensory symptoms, and no or minimal muscle weakness. Sensory GBS patient show hypo- or areflexia, distal paresthesia, and normal cerebrospinal fluid finding or albumino-cytologic dissociation which are suggesting that these conditions are a GBS variant. Autonomic dysfunctions have rarely been reported in sensory GBS patient presenting with postural hypotension, abnormal heart rate response to respiration. In this case, we demonstrate a patient with autonomic symptoms dominant sensory GBS in systemic lupus erythematosus.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy.

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes.

Corneal confocal microscopy reveals trigeminal small sensory fiber neuropathy in amyotrophic lateral sclerosis

Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing in vivo observation of corneal small sensory fibers. Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients’ corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms (with trigeminal nerve distribution), followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.

Analysis of dynein intermediate chains, light intermediate chains and light chains in a cohort of hereditary peripheral neuropathies.

The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.

Lack of transient receptor potential melastatin 8 activation by phthalate esters that enhance contact hypersensitivity in mice

We studied the involvement of sensory neurons in skin sensitization to allergens using a mouse model in which the T-helper type 2 response is essential. Skin sensitization to fluorescein isothiocyanate (FITC) has been shown to be enhanced by several phthalate esters, including dibutyl phthalate (DBP). For different types of phthalate esters, we found a correlation between the ability of transient receptor potential (TRP) A1 activation and that of enhancing skin sensitization. A TRPA1-specific antagonist, HC-030031, was shown to suppress skin sensitization in the presence of DBP. However, since phthalate esters also activate TRPV1, phthalate esters could activate other types of TRP channels non-selectively. Furthermore, sensitization to FITC is also enhanced by menthol, which activates TRPA1 and TRPM8. Here we established an in vitro system for measuring TRPM8 activation. The selectivity for TRPM8 was established by the fact that two TRPM8 agonists (menthol and icilin) induced calcium mobilization, whereas agonists of TRPA1 and TRPV1 did not. We demonstrated that phthalate esters do not activate TRPM8. TRPA1-antagonist HC-030031 did not inhibit TRPM8 activation induced by menthol or icilin. These results show that phthalate esters activate TRPA1 and TRPV1 with selectivity. TRPM8 activation is not likely to be involved in the sensitization to FITC.

Differential, size-dependent sensory neuron involvement in the painful and ataxic forms of primary Sjögren's syndrome-associated neuropathy

Primary Sjögren's syndrome (pSS)-associated neuropathy manifests a wide variety of peripheral neuropathies that may show overlap among the neuropathic forms. In this report, we describe histopathological findings of two autopsy cases with pSS-associated neuropathy; one of them manifested the painful form and another showed ataxic form. The population of dorsal root ganglion (DRG) neurons and the density of myelinated fibers in the dorsal spinal root were variably reduced among spinal segments in both forms. In the painful form, there was a prominent reduction of small neurons, while in the ataxic form, large neurons were predominately lost. In accordance with the degree of the DRG cell loss, the modality of nerve fiber loss in the dorsal spinal roots and sural nerve correlated well with the corresponding DRG neuron loss. Prominent CD8+ T lymphocyte infiltration was present in the DRG, sympathetic ganglion, epineurial and perineurial space throughout the peripheral nerve trunks, and visceral organs, including the submandibular gland of both forms.Although the size of affected DRG neurons is different, these two forms share a similar causal mechanism, namely, cytotoxic autoimmunity to ganglion neurons, which may be one of a continuum of etiological factors. This hypothesis may have an impact on therapeutic approach.

Involvement of sensory neurons in bone defect repair in rats

We investigated bone repair in sensory-denervated rats, compared with controls, to elucidate the involvement of sensory neurons. Nine-week-old male Wistar rats received subcutaneous injections of capsaicin to denervate sensory neurons. Rats treated with the same amount of vehicle served as controls. A standardized bone defect was created on the parietal bone. We measured the amount of repaired bone with quantitative radiographic analysis and the mRNA expressions of osteocalcin and cathepsin K with real-time polymerase chain reaction (PCR). Quantitative radiographic analysis showed that the standard deviations and coefficients of variation for the amount of repaired bone were much higher in the capsaicin-treated group than in the control group at any time point, which means that larger individual differences in the amount of repaired bone were found in capsaicin-treated rats than controls. Furthermore, radiographs showed radiolucency in pre-existing bone surrounding the standardized defect only in the capsaicin-treated group, and histological observation demonstrated some multinuclear cells corresponding to the radiolucent area. Real-time PCR indicated that there was no significant difference in the mRNA expression levels of osteocalcin and cathepsin K between the control group and the capsaicin-treated group. These results suggest that capsaicin-induced sensory denervation affects the bone defect repair.

Neuropathology of chronic GM2 gangliosidosis due to hexosaminidase A deficiency

Autopsy studies of late-onset GM2 gangliosidosis are sparse and only one adult case is on record. The case of partial Hex A deficiency presented here started in childhood as spinal muscular atrophy which progressed slowly over 4 decades. Cognitive function remained intact throughout the entire course, but during the last few years of life allodynia supervened. The patient died at 44 years of age. In good correlation with clinical observations the autopsy findings showed the most severe accumulation of lipid and consequent regressive change in the anterior horns of the spinal cord. Extensive but less severe storage was found in other spinal cord neurons, brain stem and selected basal ganglia. Cerebral cortex was virtually spared by storage but was the site of excessive formation of lipofuscin which was also present in many other neurons in the CNS. Marked storage and ganglionic loss was also found in the dorsal root ganglia, and the fasciculus gracilis was severely depleted of myelinated fibers. Electron microscopy showed accumulated gangliosides almost exclusively in the form of single and coalescing zebra bodies. In conclusion, the pathology in this case of chronic GM2 gangliosidosis, though in part conforming with previous observations, differed in several aspects. First, the cerebral cortex was--with only a few exceptions--free of ganglioside storage. Also spared was the cerebellum. In addition, homogeneous accumulation of zebra bodies contrasted with heterogeneity of neuronal inclusions found in other chronic cases. Finally, the involvement of sensory neurons was prominent and potentially related to allodynia. Molecular study of HEXA gene in this patient showed an TATC1278/? genotype.

‘Sensing’ autoimmunity in type 1 diabetes

Type 1 diabetes (T1D) results from autoimmune-mediated loss of insulin-producing beta-cells. Recent findings suggest that the events controlling T1D development are not only immunological, but also neuronal in nature. In the non-obese diabetic (NOD) mouse model of T1D, a mutant sensory neuron channel, TRPV1, initiates chronic, progressive beta-cell stress, inducing islet cell inflammation. This novel mechanism of organ-specific damage requires a permissive, autoimmune-prone host, but ascribes tissue specificity to the local secretory dysfunction of sensory afferent neurons. In NOD mice, normalizing this neuronal function by administration of the neurotransmitter substance P clears islet cell inflammation, reduces insulin resistance and restores normoglycemia. Here, we discuss this neuro-immuno-endocrine model, its implications and the involvement of sensory neurons in other autoimmune disorders. These developments might provide novel neuronal-based therapeutic interventions, particularly in diabetes.

Small‐fiber involvement in spinobulbar muscular atrophy (Kennedy's disease)

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA.

Nucleolar enlargement, nuclear eccentricity and altered cell body immunostaining characteristics of large-sized sensory neurons following treatment of rats with paclitaxel

Paclitaxel-induced sensory neuropathy is a problematic side-effect of cancer chemotherapy. Previous studies in rodents have shown paclitaxel treatment to have many effects on different parts of the peripheral nervous system, but those responsible for its bothersome clinical side-effects are still unclear. In the current study, we sought to obtain information about the involvement of sensory neurons in paclitaxel neurotoxicity at the level of the dorsal root ganglion. Rats were treated with a clinically relevant dose of paclitaxel (87.5 mg/m 2 weekly for a total of nine doses) to induce a sensory neuropathy; then their L5 dorsal root ganglia were studied by morphometry and immunohistochemistry. Paclitaxel treatment was generally well tolerated, and slowed conduction velocity and prolonged conduction latencies in the peripheral sensory nerves without altering conduction in the central or motor pathways of the H-reflex arc. In the L5 dorsal root ganglion, nucleolus size and the number of neurons with eccentric nuclei were increased only in a subpopulation of dorsal root ganglion neurons with cell body cross-sectional areas greater than 1750 μm 2, which made up less than 10% of the total population. Paclitaxel treatment increased immunohistochemical staining for activating transcription factor-3 (ATF-3), c-Jun and neuropeptide Y (NPY) but only in a small percentage of neuronal cell bodies and mainly in those with large cell bodies. In conclusion, we have demonstrated that nucleolar enlargement, nuclear eccentricity, ATF-3, c-Jun and NPY are neuronal markers of paclitaxel-induced sensory neuropathy, however, these axotomy-like cell body reactions are infrequent and occur in mainly large-sized sensory neurons.

Influence of Local Treatments with Capsaicin or Allyl Isothiocyanate in the Sensitization Phase of a Fluorescein-Isothiocyanate-Induced Contact Sensitivity Model

Background: In fluorescein isothiocyanate (FITC)-induced contact hypersensitivity models, dibutyl phthalate has been empirically used as a solvent ingredient. We have demonstrated that dibutyl phthalate has an adjuvant effect through the facilitation of trafficking FITC-presenting dendritic cells (DC) from the skin to draining lymph nodes. Here we investigated the effects of local pretreatment with substances that are capable of desensitizing sensory neurons in the sensitization phase. Methods: Local pretreatment of BALB/c mice with capsaicin (epicutaneous), allyl isothiocyanate (epicutaneous) or a truncated form of calcitonin gene-related peptide (CGRP_8–37; intradermal) was performed before contact sensitization to FITC. The ear swelling test was employed to monitor sensitization. The appearance of FITC-presenting CD11c-positive cells in the draining lymph nodes was detected by flow cytometry. Cytokine production in local lymph node cell cultures was determined by ELISA. Results: The ear swelling response was reduced in mice pretreated with capsaicin or allyl isothiocyanate. DC trafficking and maturation (based on the levels of costimulators CD80 and CD86) were inhibited. Interleukin-4 production by local lymph nodes was suppressed with allyl isothiocyanate but not with capsaicin. Pretreatment with CGRP_8–37 suppressed sensitization to FITC. Conclusions: Local pretreatment with substances that are capable of desensitizing sensory neurons through the respective transient receptor potential channels suppressed skin sensitization to FITC in a mouse model. This was associated with reduced trafficking and maturation of FITC-presenting DC. A CGRP antagonist also suppressed the sensitization to FITC, suggesting the possible involvement of sensory neurons in sensitization.

Upper motor neuron involvement in X-linked recessive bulbospinal muscular atrophy

ObjectiveClinicopathological findings of X-linked recessive bulbospinal muscular atrophy (SBMA) are indicative of lower motor neuron and primary sensory neuron involvement. The aim of our study was to investigate the presence of subclinical upper motor neuron (UMN) dysfunction in this disease. MethodsTwo siblings with clinical presentation, routine electrophysiological tests, histopathological features of muscle and nerve biopsies and genetic testing consistent with diagnosis of SBMA underwent transcranial magnetic stimulation (TMS). The analysed parameters were motor evoked potential (MEP) threshold, silent period (SP) and central motor conduction time. Intracortical inhibition with paired pulses from 1 to 6ms interstimulus intervals (ISIs) was evaluated in the older brother. ResultsMEP parameters were significantly altered in limb and cranial muscles and MEP suppression after paired stimulation significantly reduced in the older brother. MEP abnormalities were present in one lower limb, but SP abolished in all limbs, in the younger brother. ConclusionsSubclinical involvement of UMNs may be present in patients affected by SBMA. This finding suggests that the array of neuronal systems whose function may be affected by the pathogenic process of SBMA is larger than it was considered so far. SignificanceTMS is a sensitive diagnostic tool for the identification of UMN dysfunction and should be included in the diagnostic evaluation of patients with SBMA.

Interleukin-12 p40-homodimer production in sensory dorsal root ganglion neurons

Recently, the reports that sensory nerves contribute to induction and development of peripheral inflammation have been accumulating. Although neuropeptides have been thought to participate in modulation of inflammation, we supposed the involvement of cytokines. Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity. IL-12 is heterodimer cytokine consisting of a p35 and a p40 subunit, but the results that some of immune cell types secrete p40-homodimer have been reported. In this study, we investigated the expression and secretion of IL-12 in mouse sensory neurons in order to evaluate the involvement of sensory neurons in cell-mediated immunity. Expression of IL-12 p40 mRNA was detected and enhanced by interferon-γ (IFN-γ), but another subunit of IL-12 p35 mRNA was not detected in sensory dorsal root ganglion (DRG) neurons in culture. IL-12 p40 molecule was detected in DRG neurons by immunocytochemistry. In addition, cultured DRG neurons secreted p40-homodimer that inhibited IL-12-induced STAT4 phosphorylation in T cells. p40 mRNA expression was accumulated in DRG after administration of IFN-γ into mouse footpad, and this enhancement was eliminated by a cut of sciatic nerve. These results suggest the possibility that p40-homodimer derived from sensory nerves suppresses the excessive peripheral inflammation.

Gastric vasodilatation in the rat by cannabinoid (CB) receptor activation: Involvement of sensory neurons and nitric oxide (NO)

Background: CB receptors have been implicated in inflammation and pain. CB receptor agonists are potent vasodilators in different vascular preparations, but the mechanism of action is unclear. We investigated the effect of methanandamide, a CB receptor agonist, on the gastric vasculature of the rat stomach in vitro. In particular, we addressed the possibility that methanandamide activated capsaicin-sensitive afferent neurons which are known to release vasoactive substances upon stimulation. Methods: The rat isolated stomach was perfused via the left gastric artery with oxygenated Krebs solution by means of a peristaltic pump. Vasoconstrictor responses were recorded by an increase in intravascular pressure. The lumen of the stomach was filled with 5 ml of saline, gastric contractions being recorded by an increase in intraluminal pressure. The vasculature was precontracted by continuous infusion of methoxamine (10 ILM). Results: Vascular perfusion ofrnethanandarnide (2 or 20 ILM) and capsaicin (0.2 or 2 ILM) caused significant concentration-dependent relaxation of the precontracted va~culature\{lut ha\i no effect on gastric muscle activity. The vasorelaxant activity of n1I:thanandamide was significantly counteracted by the cannabinoid CB t receptor antagonist SR-141716A (l ILM, 30 min, about 50% inhibition) and by L-NAME, an inhibitor of nitric oxide synthase (100 ILM, 30 min, about 30% reduction). The vasorelaxant effect of capsaicin was likewise reduced in the presence of L-NAME (37% reduction) and SR141716A (33% reduction). Neither SR-141716A nor L-NAME exerted any effects per se. Conclusions: Endogenous cannabinoids as well as their receptors are present in the vasculature of the gastrointestinal tract where they are thought to playa role in inflammation and pain. From our data it is conceivable that endogenous cannabinoids activate primary sensory nerve endings in the gastric vasculature and cause vasodilatation via a NO-mediated pathway. Endogenous cannabinoids may thus be pathophysiological stimulants of capsaicin-sensitive afferent neurons that regulate local blood flow and other homeostatic mechanisms of the stomach. Supported by the Austrian Science Foundation (grant P1l834-Med) and the Jubilee Foundation of the Austrian National Bank (grant 7843)

Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity.

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10 micrograms/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500 micrograms/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.

Primary sensory neurons in X-linked recessive bulbospinal neuropathy: histopathology and androgen receptor gene expression.

Pathology of the primary sensory neurons was examined in 7 autopsied patients and 6 biopsied sural nerves from the patients with X-linked recessive bulbospinal neuronopathy (SBMA). Large myelinated fibers in the central rami (L-4 posterior root, L-4, T-7, and C-6 segment of the fasciculus gracilis), and in the peripheral rami (sural nerve) were diminished in a distally accentuated manner, while small myelinated and unmyelinate fibers were well preserved in number. Demylinating process and axonal atrophy was ubiquitous. The diameter frequency histograms of the dorsal root ganglion (DRG) neurons showed a decrease in the number of large diameter neurons and an increase in the number of small diameter neurons without substantial loss of whole number of neurons, which suggested that neuronal size was atrophied. These data suggested central and peripheral distal axonopathy with neuronal atrophy was the process of sensory neuron involvement. Expression of mutant androgen receptor mRNA with elongated CAG repeat in the DRG and sural nerve supported the view that sensory nerve involvement is the primary process in SBMA.

The Neuropeptide Substance P Stimulates Production of Interleukin 1 in Human Blood Monocytes: Activated Cells are Preferentially Influenced by the Neuropeptide

Substance P (SP) has recently been reported to induce interleukin 1 (IL-1) production by human monocytes. This was confirmed in our experiments with human monocytes cultivated in the presence of SP or SP together with lipopolysaccharide (LPS). In addition, a wide variability of cell response to the neuropeptide was noticed. Three out of twelve cell cultures were directly stimulated by SP to release IL-1, while four additional cultures needed prestimulation with suboptimal doses of LPS, and no effect was seen in the five remaining experiments. The data may suggest that preferentially activated monocytes respond to SP. The production of IL-1 by SP-stimulated monocytes is of great interest considering the broad spectrum of activity of IL-1 and the increasing evidence of sensory neuron involvement in acute and chronic inflammatory responses.