Endogenous calcitonin gene-related peptide in cerebrospinal fluid and early quality of life and mental health after good-grade spontaneous subarachnoid hemorrhage-a feasibility series.

The vasodilatory calcitonin gene-related peptide (CGRP) is excessively released after spontaneous subarachnoid hemorrhage (sSAH) and modulates psycho-behavioral function. In this pilot study, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into cerebrospinal fluid (CSF) during the acute stage after good-grade sSAH and its impact on self-reported health-related quality of life (hrQoL). Twenty-six consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out 19% (n = 5)): 35% (n = 9) underwent endovascular aneurysm occlusion, 23% (n = 6) microsurgery, and 23% (n = 6) of the patients with perimesencephalic SAH received standardized intensive medical care. An external ventricular drain was inserted within 72 h after the onset of bleeding. CSF was drawn daily from day 1-10. CGRP levels were determined via competitive enzyme immunoassay and calculated as "area under the curve" (AUC). All patients underwent a hrQoL self-report assessment (36-Item Short Form Health Survey (SF-36), ICD-10-Symptom-Rating questionnaire (ISR)) after the onset of sSAH (t1: day 11-35) and at the 6-month follow-up (t2). AUC CGRP (total mean ± SD, 5.7 ± 1.8 ng/ml/24 h) was excessively released into CSF after sSAH. AUC CGRP levels did not differ significantly when dichotomizing the aSAH (5.63 ± 1.77) and pSAH group (5.68 ± 2.08). aSAH patients revealed a higher symptom burden in the ISR supplementary item score (p = 0.021). Multiple logistic regression analyses corroborated increased mean levels of AUC CGRP in CSF at t1 as an independent prognostic factor for a significantly higher symptom burden in most ISR scores (compulsive-obsessive syndrome (OR 5.741, p = 0.018), anxiety (OR 7.748, p = 0.021), depression (OR 2.740, p = 0.005), the supplementary items (OR 2.392, p = 0.004)) and for a poorer performance in the SF-36 physical component summary score (OR 0.177, p = 0.001). In contrast, at t2, CSF AUC CGRP concentrations no longer correlated with hrQoL. To the best of our knowledge, this study is the first to correlate the levels of endogenous CSF CGRP with hrQoL outcome in good-grade sSAH patients. Excessive CGRP release into CSF may have a negative short-term impact on hrQoL and emotional health like anxiety and depression. While subacutely after sSAH, higher CSF levels of the vasodilator CGRP are supposed to be protective against vasospasm-associated cerebral ischemia, from a psychopathological point of view, our results suggest an involvement of CSF CGRP in the dysregulation of higher integrated behavior.

Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model.

Classical migraine patients experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and trigeminal cells. After CSD, ~11% of the CSF proteome is altered, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion. CSF collected from animals exposed to CSD activates trigeminal neurons in naïve mice in part by CSF-borne calcitonin gene-related peptide (CGRP). We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache.

Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF.

BACKGROUND: Administration of inflammatory soup (IS) leads to a significant release of calcitonin gene-related peptide (CGRP). Whether IS-induced CGRP release originates in primary or secondary neurons of the trigeminovascular system has not been clarified. METHODS: We determined CGRP release into the external jugular vein and in cerebrospinal fluid (CSF) following intracisternal IS administration using an in vivo rat model. We further performed polymerase chain reaction (PCR) and immunohistochemistry of the trigeminal ganglion and brainstem (trigeminal nucleus caudalis). To further elucidate a primary vs. secondary origin, experiments were repeated after neonatal capsaicin treatment (NCT) as this treatment destroys primary trigeminal afferents. RESULTS: IS-induced CGRP release into the external jugular vein and CSF were significantly reduced after NCT in both compartments but inhibition was more pronounced in jugular vein blood than in CSF. Baseline CGRP levels were not affected by NCT. PCR results show that following NCT, CGRP mRNA was significantly reduced in the trigeminal ganglion but not in the brainstem. Immunohistochemistry of the TG and brainstem support these results. CONCLUSIONS: We conclude that resting state CGRP levels can be maintained after trigeminal denervation of the meninges. However, for functional purposes primary trigeminal afferents are mandatory as they are the major source for stimulus-induced CGRP release.

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.

Cerebrospinal Fluid α-Calcitonin Gene-Related Peptide: A Comparison between Alzheimer's Disease and Multiple Sclerosis.

Alzheimer's disease (AD) and Multiple Sclerosis (MS) represent an emerging health problem on a global scale, as they are responsible for a significant contribution to the burden of disability in Western countries. Limited numbers of cerebrospinal fluid (CSF) diagnostic markers are available for each disease (amyloid and tau deposition markers for AD and oligoclonal bands for MS) representing mostly state markers that provide few, if any, clues about the severity of the clinical phenotype. α-CGRP is a neuropeptide implied in nociception, vasodilation, synaptic plasticity and immune functions. This neuropeptide is expressed in encephalic regions connected to memory, attention, autonomic and behavioral functions and is also expressed by spinal motor neurons. The present work confronted α-CGRP levels between 19 AD, 27 MS and 17 control subjects using an ELISA/EIA assay. We measured higher CSF α-CGRP contents in control subjects with respect to AD, as shown in previous studies, as well as in MS patients in comparison to AD. The control subjects and MS patients did not significantly differ between each other. We did not observe a relationship between CSF protein content, albumin quotient and α-CGRP. We also describe, retrospectively, an association between higher CSF CGRP content and higher MRI overall lesion count in MS and between lower α-CGRP and worse attention and visuo-perceptual skills in AD. We speculate that α-CGRP could be differentially involved in both disabling diseases.

Expressions and significance of calcitonin gene-related peptide and nerve growth factor in rabbit model of traumatic brain injury complicated with tibial fracture: preliminary results.

OBJECTIVE: This paper aims to establish the rabbit model of traumatic brain injury (TBI) complicated with tibial fracture and to investigate the expressions and significance of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) in cerebrospinal fluid (CSF) and serum. MATERIALS AND METHODS: 60 rabbits were randomly divided into control group, TBI group, fracture group (F group), and TBI complicated with fracture group (TBI+F group), with 15 white rabbits in each group. After modeling, the expression levels of CGRP and NGF in the CSF, and serum were detected. At the 7th week after the operation, X-ray was used to evaluate the healing of fracture rabbits. RESULTS: Serum NGF content was compared among groups at the same time point. TBI+F group had significantly higher serum NGF content than the other three groups at each time point after the operation (p<0.05). From the 3rd day after the operation, TBI group and F group had significantly higher serum NGF content than control group (p<0.05). On the 7th and 14th days after the operation, TBI group had significantly higher serum NGF content than the F group (p<0.05). The CSF NGF content in TBI group and TBI+F group showed an upward trend, and it was higher in TBI+F group and TBI group than that in F group and control group from the 7th day (p<0.05). On the 0th and 3rd days, TBI+F group had significantly higher serum NGF content than the other three groups (p<0.05). TBI+F group had a significantly higher healing number than F group on the 14th day (p<0.05). CONCLUSIONS: NGF and CGRP are mainly present in the CSF. When TBI complicated with F occurs, the serum NGF and CGRP increase, which may be involved in the fracture healing.

Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=-0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Stimulation of rat cranial dura mater with potassium chloride causes CGRP release into the cerebrospinal fluid and increases medullary blood flow.

Primary headaches may be accompanied by increased intracranial blood flow induced by the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from activated meningeal afferents. We aimed to record meningeal and medullary blood flow simultaneously and to localize the sites of CGRP release in rodent preparations in vivo and ex vivo. Blood flow in the exposed rat parietal dura mater and the medulla oblongata was recorded by laser Doppler flowmetry, while the dura was stimulated by topical application of 60mM potassium chloride (KCl). Samples of jugular venous plasma and cerebrospinal fluid (CSF) collected from the cisterna magna were analysed for CGRP concentrations using an enzyme immunoassay. In a hemisected rat skull preparation lined with dura mater the CGRP releasing effect of KCl superfusion was examined. Superfusion of the dura mater with KCl decreased meningeal blood flow unless alpha-adrenoceptors were blocked by phentolamine, whereas the medullary blood flow was increased. The same treatment caused increased CGRP concentrations in jugular plasma and CSF and induced significant CGRP release in the hemisected rat skull preparation. Anaesthesia of the trigeminal ganglion by injection of lidocaine reduced increases in medullary blood flow and CGRP concentration in the CSF upon meningeal KCl application. CGRP release evoked by depolarisation of meningeal afferents is accompanied by increased blood flow in the medulla oblongata but not the dura mater. This discrepancy can be explained by the smooth muscle depolarising effect of KCl and the activation of sympathetic vasoconstrictor mechanisms. The medullary blood flow response is most likely mediated by CGRP released from activated central terminals of trigeminal afferents. Increased blood supply of the medulla oblongata and CGRP release into the CSF may also occur in headaches accompanying vigorous activation of meningeal afferents.

Gene transfer of calcitonin gene-related peptide prevents vasoconstriction after subarachnoid hemorrhage.

We sought to determine whether adenovirus-mediated gene transfer in vivo of calcitonin gene-related peptide (CGRP), a potent vasodilator, ameliorates cerebral vasoconstriction after experimental subarachnoid hemorrhage (SAH). Arterial blood was injected into the cisterna magna of rabbits to mimic SAH 5 days after injection of AdRSVCGRP (8x10(8) pfu), AdRSVbetagal (control virus), or vehicle. After injection of AdRSVCGRP, there was a 400-fold increase in CGRP in cerebrospinal fluid. Contraction of the basilar artery to serotonin in vitro was greater in rabbits after SAH than after injection of artificial cerebrospinal fluid (P<0.001). Contraction to serotonin was less in rabbits with SAH after AdRSVCGRP than after AdRSVbetagal or vehicle (P:<0.02). Basal diameter of the basilar artery before SAH (measured with digital subtraction angiogram) was 13% greater in rabbits treated with AdRSVCGRP than in rabbits treated with vehicle or AdRSVbetagal (P:<0.005). In rabbits treated with vehicle or AdRSVbetagal, arterial diameter after SAH was 25+/-3% smaller than before SAH (P<0.0005). In rabbits treated with AdRSVCGRP, arterial diameter was similar before and after SAH and was reduced by 19+/-3% (P<0.01) after intracisternal injection of CGRP-(8-37) (0.5 nmol/kg), a CGRP(1) receptor antagonist. To determine whether gene transfer of CGRP after SAH may prevent cerebral vasoconstriction, we constructed a virus with a cytomegalovirus (CMV) promoter, which results in rapid expression of the transgene product. Treatment of rabbits with AdCMVCGRP after experimental SAH prevented constriction of the basilar artery 2 days after SAH. Thus, gene transfer of CGRP prevents cerebral vasoconstriction in vivo after experimental SAH.

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.

Triptans reduce the inflammatory response in bacterial meningitis.

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.

Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients.

Nerve growth factor (NGF) levels were determined in the CSF of patients with chronic daily headache (CDH) and correlated with levels of sensory neuropeptides. Patients with CDH showed higher NGF levels in the CSF compared with control subjects (p < 0.0001). Higher CSF levels of substance P (SP) (p < 0.002) and calcitonin-gene-related peptide (CGRP) (p < 0.0001) were also found. There was a significant positive correlation between NGF and both SP and CGRP values. These findings suggest that NGF is involved in the long-lasting sensitization and sustained activation of the trigeminal system in CDH.

Both alpha- and beta-calcitonin gene-related peptides are present in plasma, cerebrospinal fluid and spinal cord in man.

The presence of both alpha- and beta-calcitonin gene-related peptide (CGRP) was demonstrated by oxidation and by CNBr cleavage in extracts of plasma, cerebrospinal fluid and spinal cord in man. This was achieved by the use of both CNBr cleavage and oxidation of the methionine residue present in the human beta-CGRP molecule. This study demonstrates that around 50% of CGRP immunoreactivity in plasma, cerebrospinal fluid and spinal cord is not alpha-CGRP, but corresponds to beta-CGRP-like activity. Furthermore, experiments with CNBr also suggest the presence of another methionine-containing CGRP-like peptide in all three extracts.

Levels of dynorphin peptides, substance P and CGRP in the spinal cord after subchronic administration of morphine in the rat.

Rats were rendered dependent on morphine by repeated injections of morphine, in increasing doses for 14 days and sacrificed. Levels of peptides in the dorsal spinal cord and dorsal root ganglia were analyzed in rats decapitated 2 hr, 24 hr (acute abstinent) or 7 days (late abstinent) respectively, after the last injection of drug. Dynorphin A was significantly decreased in rats abstinent for 24 hr, while dynorphin B remained unaffected. Substance P and CGRP, both putative transmitters in nociceptive primary afferent neurones, and partly existing together in the same neurone, were affected differently. Significantly less substance P but unchanged levels of CGRP were detected in rats abstinent for 24 hr, while on the other hand, CGRP but not levels of substance P, were increased 2 hr after the final injection. In dorsal root ganglia, levels of substance P were lower at 2 hr, while levels of CGRP were unaffected. In late (7 days) abstinence, no effect of opiate on any peptide was detected.

The calcitonin gene-related peptide antagonist CGRP8-37 increases the latency to withdrawal responses bilaterally in rats with unilateral experimental mononeuropathy, an effect reversed by naloxone.

The present study was performed in rats with experimental mononeuropathy after left common sciatic nerve constriction. A bilateral decrease in hindpaw withdrawal latency to thermal and mechanical stimulation was observed after unilateral ligation of the left common sciatic nerve; however, it was more pronounced on the lesioned side. Compared with sham-operated rats, the content of calcitonin gene-related peptide-like immunoreactivity was significantly decreased in the left dorsal horn of the spinal cord and left dorsal root ganglia in rats with mononeuropathy. Blocking the receptor of calcitonin gene-related peptide, by intrathecal injection of 5 or 10 nmol of calcitonin gene-related peptide (8-37), induced a significant bilateral increase in hindpaw withdrawal latency to both thermal and mechanical stimulation which, however, was significantly less pronounced in mononeuropathic rats than in intact rats. The effect of calcitonin gene-related peptide (8-37) was reversed by intrathecal administration of the opioid antagonist naloxone. The contribution of calcitonin gene-related peptide and its receptors to transmission of presumed nociceptive information appears to be reduced in the sciatic nerve constriction model. The decrease in reflex responsiveness induced by calcitonin gene-related peptide (8-37) was counteracted by naloxone, indicating that opioids control the net effect of excitation in the spinal cord circuitry induced by calcitonin gene-related peptide and possibly other co-released neurotransmitters.

The effect of a single intraperitoneal dose of hrIL-1 alpha on substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity in cerebrospinal fluid, plasma and knee joint synovial fluid in the rat.

Substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) was studied in rats' cerebrospinal fluid (CSF), plasma and synovial fluid (SF) from both knee joints at 2 and 24 h following an intraperitoneal administration of 0.05 ml human recombinant interleukin-1 alpha (i.p. hrIL-1 alpha) or saline. Increased or decreased levels of SP-, NKA and CGRP-LI were detected in CSF and plasma, whereas NPY-LI was unaffected. In SF only CGRP-LI increased bilaterally. There was a correlation in CGRP-LI content between plasma and CSF following i.p. hrIL-1 alpha but not between plasma and SF or CSF and SF. It can be concluded that (1) i.p. hrIL-1 alpha activates somatosensory afferents thereby increasing SP- and CGRP-LI content in CSF and plasma and NKA-LI in CSF; 2) i.p. hrIL-1 alpha induces a bilateral increase of CGRP-LI in SF which is not mediated through systemic circulation and is possibly a part of the general host defensive reaction.

Effect of sulpiride or paroxetine on cerebrospinal fluid neuropeptide concentrations in patients with chronic tension-type headache.

In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.

Low calcitonin gene-related, peptide-like immunoreactivity in cerebrospinal fluid from chronic pain patients.

Cerebrospinal fluid (CSF) levels of calcitonin gene-related peptide-like activity (CGRP-LI), were determined in 35 patients with painful orthopaedic disorders and the activity was compared to that of 12 healthy controls without pain. Fourteen patients had pain from osteoarthritis of the hip or the knee, 11 had rhizopathic pain due to a herniated lumbar disc and 10 had pain from a hip fracture. In all patients, decreased CGRP-LI was observed in CSF compared to the controls. The lowest values were found in the patients with osteoarthritis, while there was less, but still significant, reduction of CGRP-LI in the patients with herniated lumbar disc and those with a hip fracture. In most of the patients, CGRP-LI was also analysed at a second lumbar puncture after operative treatment, when pain had subsided or was reduced. However, the CGRP-LI remained low after treatment, which may suggest the influence of factors other than pain.

Intrathecal CGRP(8-37) results in a bilateral increase in hindpaw withdrawal latency in rats with a unilateral thermal injury.

The present study was performed to explore the effects of intrathecal administration of calcitonin gene-related peptide8-37 (CGRP(8-37)) on the hindpaw withdrawal latency (HWL) to pressure in rats with one thermally injured hindpaw. Furthermore, the interaction of CGRP(8-37)and naloxone was studied. Thermal injury was performed by dipping the left paw into 60 degrees C for 20 s. This induced a significant increase in the volume of the left hindpaw (P<0.001) and significant bilateral decreases of the latency of hindpaw withdrawal response to mechanical stimulation (Left: P<0.001; right: P<0.05). Intrathecal administration of 10, 20 and 40 nmol of CGRP(8-37), but not of 1 or 5 nmol, induced a significant bilateral increase in HWLs (P<0.001). The effect of CGRP(8-37) was partly reversed by intrathecal injection of naloxone at a dose of 32 and 64 microg respectively. Using radioimmunoassay, we found a significant bilateral increase in the concentration of CGRP-like immunoreactivity in the perfusate of both hindpaws 24 h after unilateral thermal injury (left: P< 0.001; right: P< 0.05). There was also an increase in the amount of CGRP-like immunoreactivity in the cerebrospinal fluid (P< 0.001), but not in plasma. The results indicate that CGRP plays a role in the transmission of nociceptive information in the spinal cord of thermally injured rats. Furthermore, our findings suggest that opioids can modulate CGRP-related effects in the spinal cord.

Calcitonin gene-related peptide and calcitonin in the CSF of patients with dementia and depression: possible disease markers.

Cerebrospinal fluid (CSF) was obtained from 32 patients with dementia, 19 healthy controls that were age-matched with the dementia patients, and 29 DSM-IV major depression patients and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and calcitonin-like immunoreactivity (CT-LI) measured by RIA. CGRP-LI was lower in the dementia group compared to both the controls and depressed patients (P<.01) after covarying out sex and age. CT-LI was decreased in the dementia and depressed patients (P<.05) compared to the controls. A positive relationship between CGRP-LI and CT-LI was found in dementia. A logistic discriminant analysis with calcitonin gene-related peptide (CGRP) and log calcitonin (CT) predicting diagnosis (three classes) revealed a significant overall fit (chi2 = 18.08, P = .0011), with an effect test showing contributions of both independent variables: CGRP (chi2 = 10.03, P<.007), log CT (chi2 = 8.63, P = .013). In dementia, both CGRP-LI and CT-LI were decreased and their concentration ratio did not differ from that in controls, likely reflecting a general neuronal loss. Alternatively and more speculatively, but theoretically possible, expression of the alpha-CGRP/CT gene may be affected in dementia. In contrast, in depression, CT-LI but not CGRP-LI was decreased and the CGRP/CT concentration ratio was increased, which is consistent with a possibility of an altered splicing process favoring CGRP mRNA.