Clinical study of cerebrospinal fluid neuropeptides in patients with primary trigeminal neuralgia.

OBJECTIVES: To investigate the expression levels of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and ß-endorphin in the cerebrospinal fluid (CSF) and peripheral blood of patients with primary trigeminal neuralgia (TN). PATIENTS AND METHODS: We included 20 patients with primary TN who underwent percutaneous radiofrequency thermocoagulation and collected four types of samples from all of them: sample A: CSF samples; sample B: peripheral blood samples; sample C: peripheral blood samples collected one day before the operation; sample D: peripheral blood samples withdrawn one day after the operation. Another 20 CSF samples of patients with nervous system disease or gynecological disease were collected as a control (sample E). Samples A and B were obtained at the same time. We also evaluated the expression of CGRP, SP, ß-endorphin, and VIP by visual analog scale (VAS) scores one day before and one day after the operation. In addition, heart rate (HR) at baseline and at the time of sample collection, mean arterial pressure (MAP), and all side effects of the procedure were recorded. RESULTS: Significance were found concerning about CGRP, SP, ß-endorphin, and VIP in TN patients and the controls (P<0.001). The expression of CGRP, SP, and VIP in sample A was higher than that in sample E. However, the ß-endorphin level in sample A was lower than that in sample E. There was a positive correlation between sample A and B regarding the expression of CGRP, SP, ß-endorphin, and VIP (P<0. 01). There was no relationship between the time of disease onset and the expression of CGRP, SP, ß-endorphin, and VIP in sample A and sample B (P>0.05). No difference was detected between the neuropeptides levels in samples B and C (P>0.05). Notably, VAS in sample D was significantly lower than that in sample C (P<0.01). Finally, there was no difference between the intraoperative HR and MAP values in the studied samples. CONCLUSION: In primary TN patients, the blood levels of CGRP, SP, ß-endorphin, and VIP were associated with those in CSF samples. There was a significant difference between the levels of the four neuropeptides in CSF and control samples. Our results also indicated that the levels of neuropeptides in blood samples can be tested for those in CSF. The disease onset and duration exerted insignificant effects on the production and release of CGRP, SP, ß-endorphin, and VIP.

Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer's disease.

The neuropeptides substance P, orexin A (hypocretin-1) and neurotensin are signaling molecules that influence brain activity. We examined their cerebrospinal fluid (CSF) levels in a study population consisting of Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n=32), stable MCI (SMCI, n=13), other dementias (n=15), and healthy controls (n=20). CSF substance P level was increased in AD patients compared to patients with other dementias and healthy controls (P<0.05 and P<0.01, respectively). Patients with other dementia or SMCI had lower CSF orexin A level than AD patients (both P<0.05) and marginally lower level than healthy controls (both P=0.05). CSF neurotensin level was similar in all groups. In the total study population (n=80), CSF substance P level correlated positively with CSF levels of T-tau and P-tau, and in AD patients (n=32), CSF substance P level correlated positively with CSF Aß1-42 level. In conclusion, CSF substance P level was elevated in AD patients and correlated with CSF Aß1-42 level, a well established marker of senile plaque pathology. The role of low CSF orexin A level in other dementias or SMCI needs to be explored in further studies.

Antinociceptive effects of endomorphin-2: suppression of substance P release in the inflammatory pain model rat.

Endomorphin-2 (EM2) and Substance P (SP) exert suppressive and facilitative influences upon nociception, respectively. Although EM2 and SP were often co-expressed in single neurons in dorsal root ganglion (DRG), it is still unknown if and how the nociception-suppressive influences of EM2 might be exerted upon nociception-facilitative effects of SP in the DRG neurons. We examined these issues in the inflammatory pain model rats produced by subcutaneous injection of the complete Freund's adjuvant into the hind paw. The paw withdrawal threshold for mechanical allodynia was measured. Changes of EM2 and SP release were estimated by measuring intrathecal levels of EM2 and SP through in vivo microdialysis analysis of cerebrospinal fluid. The mechanical allodynia was dose-dependently attenuated by intrathecal injection of EM2 or a neurokinin-1 receptor antagonist, and facilitated by intrathecal injection of SP or a mu-opioid receptor (MOR) antagonist. Importantly, intrathecal level of SP was found to be lowered by intrathecal injection of EM2. Morphologically, colocalization of EM2-, MOR- and SP-immunoreactivity in single DRG neurons was observed by immunofluorescent histochemistry, and co-expression of EM2 and SP in large, dense-cored presynaptic vesicles in primary afferents, as well as localization of MOR on pre- and postsynaptic membrane in spinal dorsal horn, was also confirmed electron miscroscopically. Thus, the results indicated that analgesic influences of EM2 upon inflammatory pain might be exerted through suppression of SP release, supporting the assumptions that binding of EM2 to presynaptic MOR might induce such effects.

Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.

OBJECTIVE: Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF). DESIGN: Cross-sectional, comparative, observational study. SUBJECTS: Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included. METHODS: Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit. RESULTS: We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs. rs = 0.574, P = 0.032). CONCLUSIONS: Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

A potential role for substance P and interleukin-6 in the cerebrospinal fluid of Cavalier King Charles Spaniels with neuropathic pain.

BACKGROUND: Neuropathic pain can be a clinical sign in Cavalier King Charles Spaniels (CKCS) with syringomyelia. The pathophysiology of this pain is not fully understood. HYPOTHESIS: Neuropathic pain in CKCS is a result of a neuroinflammatory process. ANIMALS: Twenty-six client-owned dogs: 15 dogs with clinical signs of cervical hyperesthesia (group 1), and 11 dogs without of clinical signs (group 2). METHODS: Dogs were examined by magnetic resonance imaging (MRI). Interleukin-6, tumor necrosis factor alpha, and substance P were measured in CSF and compared with morphological findings on MRI and clinical pain scores. RESULTS: All dogs without clinical signs had symmetrical syringomyelia, whereas in the group with pain, 6 dogs had symmetrical and 9 dogs had asymmetrical syringomyelia. Pain and syringomyelia asymmetry were correlated, and a strong association between pain and dorsal horn involvement of syringomyelia was observed. There was no significant difference between the mean width of the syringomyelia in dogs with or without pain. The concentrations of interleukin-6 and substance P were significantly higher in dogs with neuropathic pain. Tumor necrosis factor alpha was not detected in either group. Concentrations of substance P were significantly higher in dogs with asymmetrical syringomyelia or dorsal horn involvement, whereas interleukin-6 concentrations were not significantly different between groups. CONCLUSION: Release of interleukin-6 and substance P may initiate proinflammatory effects leading to development of persistent pain in CKCSs with syringomyelia.

Cerebrospinal fluid substance P-like immunoreactivity correlates with aggression in personality disordered subjects.

BACKGROUND: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters; some seem to play an inhibitory role, whereas others seem to play a facilitory role in the modulation of aggression. Laboratory animal studies of substance P suggest a facilitory role for this undecapeptide in the modulation of aggression, but no studies of substance P have yet been reported with regard to human aggression. METHODS: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with personality disorder (PD) and substance P-like immunoreactivity was measured and correlated with measures of aggression and impulsivity. RESULTS: The cerebrospinal fluid substance P-like immunoreactivity levels were directly correlated with a composite measure of aggression and, more specifically, with Buss-Durkee Aggression. No correlation was seen with any measure of impulsivity or of general dimensions of personality. CONCLUSIONS: These data suggest a direct relationship between central nervous system substance P containing neural circuits and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of impulsive aggression in human subjects.

Cerebrospinal fluid neurotransmitter changes during the perioperative period in patients undergoing total knee replacement: a randomized trial.

BACKGROUND: Total knee replacement (TKR) is of enormous benefit to patients with osteoarthritis of the knee; however, the acute postoperative pain can be severe and difficult to manage. The role of major spinal cord neurotransmitters in this acute postoperative period is not clear, although there are a few studies in humans. We performed the first prospective clinical study undertaken to delineate the changes in the spinal neurotransmitters after a surgery such as TKR. Furthermore, we also determined whether antihyperalgesic drugs at clinically acceptable doses modulate spinal neurotransmitter concentrations in patients during the perioperative period. METHODS: All patients had a spinal needle placed in the lumbar region and cerebrospinal fluid (CSF) obtained for baseline measurement of the neurotransmitters. An intrathecal catheter was then placed for spinal anesthesia for standard TKR and for continuous spinal postoperative analgesia. The spinal catheter was also used postoperatively to sample CSF at 2, 4, 8, 12, 24, and 32 hours after catheter placement. CSF samples were assayed for norepinephrine, substance P, calcitonin gene-related peptide (CGRP), and glutamate concentrations. SF-36 (36-item Short Form Health Survey) was measured preoperatively. Numerical rating scale (NRS) pain scores and intrathecal analgesic consumption were recorded postsurgery at 4-hour intervals for 32 hours. We performed a randomized, placebo-controlled, double-blind trial with 3 drug groups (n = 16 per group): placebo; single-dose pregabalin (150 mg administered before surgery); and multidose pregabalin (150 mg administered presurgery and 12 and 24 hours later), to determine the effect of an antihyperalgesic drug such as pregabalin on spinal neurotransmitters. RESULTS: Forty-eight patients were randomly assigned to the 3 perioperative treatment groups, and multiple CSF samples were successfully obtained from 44 patients. Before surgery, increased bodily pain (from preoperative SF-36 measure) was correlated with increased CSF norepinephrine concentration (P = 0.044). Compared with presurgery values, norepinephrine levels were lower in the placebo group at the 2- and 4-hour time points (P < 0.005) whereas in the single and multidose groups, the reduction (P < 0.001) continued until 12 and 24 hours, respectively. Substance P CSF levels had an early peak value (at 2 hours) in all 3 groups, and then returned to baseline. Compared with baseline value, the CGRP CSF levels only decreased at the 32-hour time point in the placebo group, but in both pregabalin groups, CGRP levels decreased over the 4- to 32-hour period. In the placebo group only, CSF glutamate decreased over 4 to 32 hours compared with presurgery values. However, there was no difference in the CSF neurotransmitter concentrations among the 3 treatment groups over the 32-hour sampling period. In the placebo group, the early NRS pain score area under the curve, AUC [0-12 hours], was positively correlated (R = 0.67, P = 0.0088) with the CSF norepinephrine concentration AUC [12-24 hours], but none of the other neurotransmitters was correlated with the NRS. None of the CSF neurotransmitter concentrations correlated with postoperative analgesic consumption. CONCLUSION: In the perioperative period, the concentration changes of the 4 spinal neurotransmitters have a distinct time course. CSF substance P seems to increase very rapidly with surgical intervention, whereas the CSF norepinephrine concentration tends to decrease. At clinical doses, pregabalin does not seem to modulate these spinal neurotransmitter concentrations.

Pemirolast reduces cisplatin-induced kaolin intake in rats.

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial.

The substance P-neurokinin-1 receptor (SP-NK(1)R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK(1)R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK(1)R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786).

Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered concentrations of stress-related neurohormones, neurotrophins, and neuropeptides in plasma and serum; however, few studies have examined central alterations of these measures in individuals with PTSD. Furthermore, no study to date has evaluated the effects of successful antidepressant treatment on cerebrospinal fluid (CSF) abnormalities in PTSD. METHOD: Sixteen medication-free outpatients with chronic PTSD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) due to physical and/or sexual abuse or motor vehicle accidents (mean ± SD age = 36 ± 11.4 years, 12 women) and 11 nontraumatized healthy subjects (mean ± SD age = 35.3 ± 13.1 years, 7 women) underwent a lumbar puncture for collection of CSF. Seven PTSD patients had a repeat lumbar puncture 12 weeks later, after successful treatment of PTSD with paroxetine. CSF was analyzed for corticotropin-releasing factor (CRF), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and substance P concentrations. The study was conducted between January 2003 and August 2004. RESULTS: Compared to nontraumatized healthy controls, patients with chronic PTSD had similar pretreatment concentrations of CSF CRF, IL-6, BDNF, IGF-1, and substance P. Posttreatment CSF measures did not change significantly in patients whose symptoms remitted with paroxetine. CONCLUSIONS: Chronic, moderate PTSD due to civilian trauma, without psychotic symptoms and without significant rates of comorbid depression, alcohol dependence, or substance dependence, is not associated with abnormalities in CSF CRF, IL-6, BDNF, IGF-1, or substance P levels. Despite substantial reduction in PTSD symptoms, antidepressant treatment does not alter normal central concentrations of these neurochemicals, with the possible exception of substance P.

Propofol/alfentanil and propofol/ketamine procedural sedation in children with acute lymphoblastic leukaemia: safety, efficacy and their correlation with pain neuromediator expression.

Invasive procedures, such as the lumbar puncture, can cause anxiety and pain in children undergoing treatment for acute lymphoblastic leukaemia (ALL). We investigated the safety and efficacy of two different protocols for analgo-sedation in 20 children with ALL undergoing lumbar puncture. We have conducted a prospective, cross-over study. Protocol A was composed of an association between propofol and alfentanil. Protocol B consisted in the combination of propofol and ketamine. We also evaluated the levels of nerve growth factor, substance P and enkephalins in the cerebrospinal fluid of these patients. All patients showed a satisfactory sedation and analgesia. We found a statistically significant difference of vital parameters between protocol A and protocol B, while there were no significant differences between sedation scores and the other parameters evaluated. Patients in protocol A showed a higher incidence of major side effects, such as respiratory depression. Pain neuromediator levels did not show any statistical difference between the two groups. This study shows that both protocols are effective to obtain a good sedation and analgesia in children with ALL undergoing lumbar puncture, but the association between propofol and ketamine appears to be safer due to the lower incidence of side effects.

Plasma and cerebrospinal fluid substance P in post-stroke patients with depression.

AIMS: To investigate the correlation between the incidence of post-stroke depression (PSD) and the levels of substance P (SP) in the plasma and cerebrospinal fluid (CSF). METHODS: Ninety-one stroke patients were divided into PSD (n = 46) and post-stroke (without depression) groups (n = 45). PSD must have occurred 2-4 weeks after the onset of the stroke and was determined by the Hamilton Rating Scale for Depression (HAMD). In addition, the subjects were divided into anterior (n = 67) and posterior circulation stroke groups (n = 24) based on the location of the focus as determined by computed tomography. All recruited patients were graded by the National Institutes of Health Stroke Scale (NIHSS). RESULTS: The results included the following findings: (i) the level of plasma SP in the PSD group (58.47 +/- 14.39) was higher than that of the PS group (36.98 +/- 9.49; P = 0.000), while the level of CSF SP in the PSD group (72.13 +/- 13.06) was higher than that of the post-stroke group (37.30 +/- 12.57; P = 0.03); (ii) the level of plasma SP was positively correlated with the HAMD and NIHSS score; (iii) the level of plasma SP (38.45 +/- 12.23), the HAMD score (9.08 +/- 8.72), and the NIHSS score (3.25 +/- 1.90) of the anterior stroke group (51.21 +/- 16.27, 17.46 +/- 15.96, and 6.91 +/- 3.30, respectively) were higher than those of the posterior stroke group (38.45 +/- 12.23, 9.08 +/- 8.7, and 3.25 +/- 1.90, respectively; P = 0.017, P = 0.001, and P = 0.000, respectively). CONCLUSIONS: SP in the plasma and CSF of patients exhibited a close correlation with neural damage and the incidence of PSD. This study also suggested that anterior hemispheric strokes may play a significant role in development of PSD.

Fibromyalgia: an update and immunological aspects.

Fibromyalgia syndrome (FMS) is now understood as a chronic pain syndrome, and recent evidence indicates it is not a pure psychosomatic disorder. We review the current knowledge in FMS pain pathways, focusing on the central system sensitization phenomenon and the abnormalities in the inhibitory pain systems. Chronic headache is one of the most common symptoms in FMS, and better knowledge of their common pathophysiologic features can help us understand both conditions better. These features include the nerve growth factor actions and failure of the endocannabinoid system. In addition, we review new immunological aspects of FMS, both in their humoral (autoantibodies, antipolymer antibodies) and cytokine (interleukin-2) aspects.

Decreased cerebrospinal fluid concentrations of substance P in treatment-resistant depression and lack of alteration after acute adjunct vagus nerve stimulation therapy.

Recent preclinical and clinical research has demonstrated that the neuropeptide substance P (SP) plays a role in the central nervous system (CNS) response to stress, and perhaps in the etiology of major depression and/or anxiety disorders. The nature of this role, however, is poorly understood. A limited body of evidence suggests that in medication-free depressed patients, cerebrospinal fluid (CSF) concentrations of SP may be elevated relative to healthy controls. Two studies have shown that antidepressant treatment does not significantly change CSF concentrations of SP. Using standard lumbar puncture techniques, baseline CSF samples were obtained from 19 medication-free healthy controls and 19 medicated patients with treatment-resistant depression (TRD). Mean CSF SP concentration was significantly lower in TRD patients on psychotropic medications than in the group of healthy subjects. After 10-12 weeks of treatment with adjunct vagus nerve stimulation (VNS), CSF SP concentrations were not significantly changed. Low CSF SP may reflect a biological marker of the subtype of severe and chronic depression that is resistant to standard therapies.

Fibromyalgia--management of a misunderstood disorder.

PURPOSE: The purpose of this article is to review (a) what is currently known about the pathophysiology of fibromyalgia (FM), (b) how to identify patients who are susceptible to this disorder, and (c) the recommended pharmacological and nonpharmacological treatment options. DATA SOURCES: Data sources include reviews and original research from scholarly journals and Internet sites. CONCLUSIONS: There are approximately 6 million individuals in the United States diagnosed with FM, making it the third most prevalent rheumatologic disorder in this country. Failure to identify a specific causal mechanism for FM has resulted in a shift in the focus of research from etiology to treatment (Baumstark & Buckelew, 2002). Based on the literature, the most successful interventions for reduction of chronic symptoms in the FM patient is a combination of education, psychological assistance, and exercise, along with medications. It is essential that nurse practitioners (NPs) understand the issues and concerns of patients afflicted with this complex disorder. Although the organic etiology of FM syndrome remains unclear, the goals of treatment are to control pain and improve adjustment, well-being, and daily functioning of these patients to the maximum extent possible. IMPLICATIONS FOR PRACTICE: NPs are in a unique position to help identify patients who may be suffering from FM or those diagnosed with FM reporting inadequate relief of symptoms. The incomplete understanding of the biological underpinnings, as well as the multiple symptoms that characterize FM syndrome, make it a challenging disorder to diagnose and treat. It takes time and patience to care for FM patients, and there are no "quick fixes." Diagnosis is made by a combination of patient history, physical examination, laboratory evaluations, and exclusion of other causes of symptoms confused with FM. Understanding the symptomology and recommended treatments will allow NPs to give appropriate care that may include making referrals for multidisciplinary treatment of these complex patients.

Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression.

OBJECTIVE: The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. METHOD: The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. RESULTS: Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. CONCLUSIONS: These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans.

Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs.

Intrathecal (IT) substance P-Saporin (SP-SAP), a 33-kDa-targeted neurotoxin, produces selective destruction of superficial neurokinin 1 receptor (NK1r)-bearing cells in the spinal dorsal horn. In rats, SP-SAP prevents the formation of hyperalgesia and can reverse established neuropathic pain behavior in rodents. To determine the safety of this therapeutic modality in a large animal model, beagles received bolus IT lumbar injections of vehicle, SP-SAP (1.5, 15, 45, or 150 microg), or a nontargeted preparation of saporin (SAP, 150 microg) for immunohistological analysis of spinal cords. Doses of 15 microg SP-SAP and above produced a significant and equivalent loss of NK1r-bearing cells and dendrites in lumbar laminae II and I compared to vehicle- or SAP-treated animals. Cervical regions in all animals displayed no loss of NK1r immunoreactivity as compared to controls. Total numbers of neurons in the lumbar dorsal horn or alpha-motor neurons in the ventral horn demonstrated no significant changes. No increases in the astrocytic marker glial fibrillary acidic protein were noted following treatment with SP-SAP, suggesting a lack of generalized neurotoxicity. Additional dogs received doses of 1.5-150 microg SP-SAP or SAP and were sacrificed after 28 or 90 days to assess behavioral and physiological parameters. Although some acute motor signs were observed with both SP-SAP and SAP, no long-lasting significant events were noted in any of these animals. These data indicate no adverse toxicity at doses up to 10 times those necessary for producing loss of superficial NK1r-bearing neurons in a large animal model.

Substance P in serum and cerebrospinal fluid of depressed patients: no effect of antidepressant treatment.

The neuropeptide substance P (SP) and its receptor, the neurokinin receptor-1 (NK-1), have been associated with some aspects of the pathophysiology of depression. There is limited information available about the effects of antidepressant treatment on serum and cerebrospinal fluid (CSF) concentrations of SP. We measured serum levels of SP in 78 depressed patients after a 6-day medication washout period, as well as after 14 and 35 days of antidepressant treatment with either paroxetine or amitriptyline. In 11 patients, SP was determined in CSF both before and after treatment. Eleven healthy male subjects served as controls. Baseline SP concentrations were independent of age, gender and severity of depression. Neither the total group nor subgroups showed significant differences in SP serum concentrations. SP concentrations in CSF did not change significantly in the patients during treatment, but there was a trend for an increase in paroxetine-treated patients. Serum SP concentrations were not related to treatment response or the class of antidepressant administered. Our data do not support the hypothesis that changes in SP levels in serum or CSF are related to antidepressant response.

Cerebrospinal neuropeptide Y and substance P in suicide attempters during long-term antidepressant treatment.

This study describes cerebrospinal fluid (CSF), neuropeptide Y (NPY) and substance P (SP) in patients with a recent suicide attempt and during antidepressant treatment. Seven out of 13 patients received antidepressants. The patients were examined on three separate occasions, i.e. at pre-treatment, followed by every 3 or 4 months. Antidepressant treatment seemed to affect the levels of CSF NPY, which decreased significantly between the second and last lumbar puncture despite no significant changes of clinical scores. When the whole group was taken into consideration, both CSF NPY and SP decreased significantly. At pre-treatment, Brief Scale of Anxiety scores were significantly and negatively correlated to CSF SP and tended to be negatively correlated to CSF NPY. There were also significant positive correlations between CSF NPY and SP during the entire study in the whole group, possibly reflecting an inter-relationship between these neuropeptides.