European Academy of Neurology guideline on trigeminal neuralgia.

BACKGROUND AND PURPOSE: Trigeminal neuralgia (TN) is an extremely painful condition which can be difficult to diagnose and treat. In Europe, TN patients are managed by many different specialities. Therefore, there is a great need for comprehensive European guidelines for the management of TN. The European Academy of Neurology asked an expert panel to develop recommendations for a series of questions that are essential for daily clinical management of patients with TN. METHODS: A systematic review of the literature was performed and recommendations was developed based on GRADE, where feasible; if not, a good practice statement was given. RESULTS: The use of the most recent classification system is recommended, which diagnoses TN as primary TN, either classical or idiopathic depending on the degree of neurovascular contact, or as secondary TN caused by pathology other than neurovascular contact. Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN. If MRI is not possible, trigeminal reflexes can be used. Neurovascular contact plays an important role in primary TN, but demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression. In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used. For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice. Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy. It is recommended that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated. Microvascular decompression is recommended as first-line surgery in patients with classical TN. No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN. Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact. Treatment for patients with secondary TN should in general follow the same principles as for primary TN. In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support. CONCLUSIONS: Compared with previous TN guidelines, there are important changes regarding diagnosis and imaging. These allow better characterization of patients and help in decision making regarding the planning of medical and surgical management. Recommendations on pharmacological and surgical management have been updated. There is a great need for future research on all aspects of TN, including pathophysiology and management.

Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). METHODS: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. RESULTS: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. CONCLUSIONS: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH.

Prospective Safety Study of Intrathecal Gadobutrol in Different Doses.

BACKGROUND AND PURPOSE: In our clinical practice, we increasingly use intrathecal contrast-enhanced glymphatic MR imaging to assess CSF disturbances. However, because intrathecal MR imaging contrast agents such as gadobutrol (Gadovist; 1.0 mmol/mL) are used off-label, a thorough understanding of the safety profile is required. MATERIALS AND METHODS: We performed a prospective safety study from August 2020 to June 2022 of intrathecal gadobutrol, including consecutive patients who received either 0.50, 0.25, or 0.10 mmol. Serious and nonserious adverse events were recorded systematically at 1-3 days, 4 weeks, and >6 months after the intrathecal administration. RESULTS: The study included 196 patients who received intrathecal gadobutrol, including patients assessed for idiopathic normal pressure hydrocephalus (iNPH, n = 144) or patients examined for other CSF disorders (non-iNPH cohort; n = 52). The intrathecal gadobutrol doses were either 0.50 mmol (n = 56), 0.25 mmol (n = 111), or 0.10 mmol (n = 29). No serious adverse events were observed. Nonserious adverse events on days 1-3 after intrathecal gadobutrol were, to some degree, dose-dependent but mild-to-moderate, including severe headache, nausea, and/or dizziness in 6/196 (6.3%) patients, and they were more common in the non-iNPH than in the iNPH cohort. At 4 weeks, none reported severe nonserious adverse events, and 9/179 (5.0%) patients had mild-to-moderate symptoms. After >6 months, 2 patients reported mild headache. CONCLUSIONS: The present study adds to the accumulating evidence that intrathecal gadobutrol in doses up to 0.50 is safe.

Arterial blood pressure vs intracranial pressure in normal pressure hydrocephalus.

OBJECTIVE: To characterize the association between arterial blood pressure (ABP) and intracranial pressure (ICP) in idiopathic normal pressure hydrocephalus (iNPH) patients, and its impact on outcome of shunt surgery. MATERIALS AND METHODS: We analyzed all 35 iNPH patients whose ABP and ICP were recorded simultaneously during 6 years (2002-2007). The static and pulsatile pressures were averaged over consecutive 6-s intervals; the moving correlations between ICP and ABP (static and pulsatile) were determined during consecutive 4-min periods to explore time-related variations. RESULTS: Neither static nor pulsatile ABP were altered in iNPH shunt responders. Elevated pulsatile ICP, but normal static ICP, was seen in responders. The time-varying correlations of static and of pulsatile pressures were generally low, and did not differ between shunt responders/non-responders. CONCLUSIONS: In iNPH shunt responders, static or pulsatile ABP were not altered and only pulsatile ICP was elevated.

Five-year incidence of surgery for idiopathic normal pressure hydrocephalus in Norway.

OBJECTIVES: We have previously determined the incidence and prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the county of Vestfold in Norway. This study aimed at determining the incidence of surgeries for iNPH. MATERIALS AND METHODS: Information about age, sex, operation year and operation type was collected retrospectively for all patients hospitalized from 2002 to 2006 with any diagnosis of iNPH and operated with insertion of a ventriculo-peritoneal or ventriculoatrial shunt system, or with endoscopic third ventriculostomy in any of Norway's five regional neurosurgical centers. RESULTS: Two hundred fifty-two patients were operated during the 5-year period, making the total incidence 1.09/100,000/year. The yearly incidence ranged from a minimum of 0.84/100,000 in 2006 to a maximum of 1.47/100,000 in 2004. The incidence was highest in the age group 70-79 years. There were little regional differences regarding incidence, sex, and age and operation type. CONCLUSIONS: The data suggest that too few patients are being offered surgical treatment for iNPH in Norway.

Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients.

BACKGROUND AND PURPOSE: Intrathecal contrast-enhanced glymphatic MR imaging has shown promise in assessing glymphatic function in patients with dementia. The purpose of this study was to determine the safety profile and feasibility of this new MR imaging technique. MATERIALS AND METHODS: A prospective safety and feasibility study was performed in 100 consecutive patients (58 women and 42 men, 51 ± 19 years of age) undergoing glymphatic MR imaging from September 2015 to August 2018. Short- and long-term serious and nonserious adverse events were registered clinically and by interview after intrathecal administration of 0.5 mL of gadobutrol (1.0 mmol/mL) along with 3 mL of iodixanol (270 mg I/mL). Adverse events are presented as numbers and percentages. RESULTS: One serious adverse event (anaphylaxis) occurred in a patient with known allergy to iodine-containing contrast agents (1%). The main nonserious adverse events during the first 1-3 days after contrast injection included severe headache (28%) and severe nausea (34%), though the frequency depended heavily on the diagnosis. After 4 weeks, adverse events had resolved. CONCLUSIONS: Intrathecal administration of gadobutrol in conjunction with iodixanol for glymphatic MR imaging is safe and feasible. We cannot conclude whether short-duration symptoms such as headache and nausea were caused by gadobutrol, iodixanol, the lumbar puncture, or the diagnosis. The safety profile closely resembles that of iodixanol alone.

Assessment of idiopathic normal pressure patients in neurological practice: the role of lumbar infusion testing for referral of patients to neurosurgery.

BACKGROUND AND PURPOSE: In neurological practice patients with tentative idiopathic normal pressure hydrocephalus (iNPH) usually are referred to neurosurgery based on clinical and radiological findings. Hydrodynamic assessment using lumbar infusion testing might be helpful in selecting patients. To retrospectively analyse lumbar infusion tests done in neurological practice in iNPH patients to see how infusion test results relate to the clinical course and shunt response. MATERIALS AND METHODS: Sixty-three consecutive patients with Possible/Probable iNPH were tested during a 1-year period. The pre-operative lumbar infusion tests were assessed according to two strategies: (i) Determining the resistance to cerebrospinal fluid (CSF) outflow (R(out)). (ii) Quantification of the CSF pressure (CSFP) pulsatility during lumbar infusion (Q(pulse)). The results were related to the prospectively followed clinical course and shunt response after 12 months. RESULTS: The lumbar infusion-derived parameters R(out) and Q(pulse) related weakly. Shunt response after 12 months was not related to R(out), but was highly related to the Q(pulse). False negative results of lumbar infusion testing were observed in 16% of the patients. DISCUSSION: In neurological practice lumbar infusion testing may be useful for determining which patients to refer to neurosurgery. Our data favour determination of CSFP pulsatility (Q(pulse)) rather than R(out) for prediction of shunt response.

Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population.

OBJECTIVE: The clinical condition normal pressure hydrocephalus (NPH) is one of the few conditions with dementia that can be successfully treated. Even though NPH was described more than 40 years ago, information on prevalence and incidence of this disease is scarce. The objective of this study was to obtain information about prevalence of iNPH in a Norwegian population. METHODS: In a stable population of 220,000 inhabitants, structured and intensive efforts were directed towards the public via local newspapers, radio and television channels, and directed towards the healthcare professionals via personal letters and lectures, to recruit patients with idiopathic NPH (iNPH) investigation during a 12-month period. This population is served by only one neurological department and one neurosurgical department, thus avoiding any leakage of patients during the investigation period. We determined those patients fulfilling the diagnostic criteria of probable iNPH. RESULTS: Eighty-six patients were referred, of whom 48 patients fulfilled the diagnostic criteria of probable iNPH. This equals a minimum prevalence of iNPH in our population of 21.9/100,000. Most importantly, the prevalence was increasing with age. When excluding patients who had symptoms for more than 1 year, we found an incidence of 5.5/100,000/year. CONCLUSIONS: In this Norwegian population of 220,000 inhabitants, we found a prevalence of probable iNPH of 21.9/100,000 and an incidence of 5.5/100,000. The numbers should be regarded as minimum estimates.

Rapid and severe rise in static and pulsatile intracranial pressures during a generalized epileptic seizure.

In a patient with no prior history of seizures we were able to record static (mean) intracranial pressure (ICP) and pulsatile ICP (mean ICP wave amplitude) continuously during a first-time generalized epileptic seizure. The patient experienced episodic headache five months after a subarachnoid haemorrhage. In order to rule out low-pressure hydrocephalus she was admitted for a 24-hour intracranial pressure registration. ICP parameters were normal prior to the seizure. We observed an immediate and enormous rise in both static (mean) ICP and pulsatile ICP (mean ICP wave amplitude). Mean ICP and ICP wave amplitude peaked at 93 mmHg and 22 mmHg, respectively. Pulsatile ICP remained elevated after normalization of static ICP and may indicate impairment of intracranial compliance even after the static ICP was normalized.

Microvascular decompression for hemifacial spasm: postoperative neurologic follow-up and evaluation of life quality.

Microvascular decompression (MVD) is an effective and safe treatment in hemifacial spasm (HFS). Postoperative evaluations are usually made by neurosurgeons. Follow-up studies performed by neurologists and postoperative quality of life (QoL) investigations are lacking. All 25 HFS patients operated with MVD in our centre between 2000 and 2004 were evaluated with the recently validated HFS-7 scheme, extended with the item 'sleep disturbance due to HFS' (HFS-8). The patients underwent a careful neurological examination median 3 years after the operation. The evaluation focused on clinical aspects, changes in blood pressure and time until observable effect of MVD. The evaluation of HFS-7 questionnaire and the extended form (HFS-8) showed significant improvement in QoL after MVD. Neurological outcome was in almost all cases excellent or good. Eleven (44%) patients had no neurological deficits at all. Only one patient had serious complications with ipsilateral facial palsy, deafness, balance problems and vertigo. The other patients had minor neurological findings or symptoms. Eighteen (72%) patients experienced early effect within 3 months after MVD; seven (28%) patients had late effect between 6 and 14 months. Median age of the patients with late effect (62.6 years) was significantly higher than in those with early effect (52.7 years).

Association among intracranial compliance, intracranial pulse pressure amplitude and intracranial pressure in patients with intracranial bleeds.

OBJECTIVE: To investigate the association among intracranial compliance (ICC), intracranial pulse pressure amplitude and intracranial pressure (ICP) in patients with intracranial bleeds. METHODS: Five patients with intracranial bleeds had their ICC and ICP monitored during days 1-8 after ictus. The recordings were stored as raw data files and analysed retrospectively. The parameters mean ICC, mean ICP wave amplitude and mean ICP were determined and average values were calculated in 1 hour time periods. RESULTS: A total of 262 1 hour recordings were analysed. There was a significant correlation between mean ICC and mean ICP wave amplitude and between mean ICC and mean ICP. The mean ICP wave amplitude was significantly higher during the 1 hour periods with mean ICC<0.5 ml/mmHg and significantly lower during 1 hour periods with mean ICC 1.5-3.0 ml/mmHg. Correspondingly, in the 159 1 hour recordings with mean ICP wave amplitude> or =5.0 mmHg, mean ICC was significantly lower than in the 103 recordings with mean ICP wave amplitude<5.0 mmHg. Mean ICP was normal (i.e. <20 mmHg) in 260 of 262 (99.2%) of the 1 hour recordings; in the 49 1 hour recordings with mean ICP>15 mmHg, mean ICC was significantly lower than in the 213 recordings with mean ICP<15.0 mmHg. CONCLUSION: In this cohort of pressure recordings, there was a strong association between ICC and intracranial pulse pressure amplitude. There also was a strong association between ICC and mean ICP, but mean ICP was normal in 260 of 262 1 hour recordings (99.2%).

Association between intracranial, arterial pulse pressure amplitudes and cerebral autoregulation in head injury patients.

OBJECTIVE: To explore whether intracranial pulse pressure amplitudes relate to arterial pulse pressure amplitudes and whether correlations between time-related changes in intracranial and arterial pulse pressure amplitudes associate with indices of cerebral autoregulation. METHODS: A total of 257 continuous and simultaneous intracranial pressure (ICP), arterial blood pressure (ABP) and middle cerebral artery (MCA) blood velocity recordings were obtained 1-14 days after ictus in 76 traumatic head injury patients and analysed retrospectively. Clinical outcome was assessed using the Glasgow outcome scale (GOS). Pulse pressure amplitudes of corresponding single ICP and ABP waves were correlated in consecutive 200 wave pairs. Mean ICP, mean ABP and mean ICP wave amplitudes, and mean and systolic MCA blood flow velocities, were computed in consecutive 6 second time windows. The indices of cerebral autoregulation PRx (moving correlation between mean ICP and mean ABP), and Mx and Sx (moving correlation between mean and systolic MCA blood velocity and cerebral perfusion pressure) were calculated over 4 minute periods and averaged over each recording. RESULTS: Intracranial pulse pressure amplitudes were not related to arterial pulse pressure amplitudes (mean of Pearson's correlations coefficients: 0.04). Outcome was related to mean ICP, PRx and Sx (p

Is intracranial pressure waveform analysis useful in the management of pediatric neurosurgical patients?

BACKGROUND: We have reported casuistic observations that intracranial pressure (ICP) waveform analysis may be useful in the management of pediatric patients. METHOD: We here report our whole patient material of 65 children undergoing ICP monitoring with storage of their ICP raw data files during the years 2002-2005. We retrospectively explored the clinical symptoms/findings and radiological cerebral ventricular size before ICP monitoring. Mean ICP was the actively treated ICP parameter. Using an algorithm for identification of cardiac-beat-induced pressure waves we retrospectively determined the mean ICP wave amplitude and latency, in addition to mean ICP. Outcome with regard to change in symptoms/findings during a 1-year period was determined in 55 children. RESULTS: The material includes children with hydrocephalus, craniosynostosis, shunt failure, benign intracranial hypertension and others. The ICP recordings gave wrong diagnostic information due to bad signal quality in 5 of 65 patients (7.7%). The mean ICP wave amplitude was increased in those with papilledema, lethargy and nausea. The main observations were that the mean ICP wave amplitude (not mean ICP) was increased in those that improved from clinical symptoms/findings after treatment and in those that were unchanged/worse after not being treated. CONCLUSIONS: Waveform analysis with computation of the mean ICP wave amplitude was more useful by providing information about the quality of the ICP recording, by comparing better with the symptoms/findings at the time of ICP monitoring and by best predicting outcome. Most significantly, 14 of 55 patients (25%) with high amplitudes and left untreated did not recover spontaneously.

Aqueductal Stroke Volume: Comparisons with Intracranial Pressure Scores in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Aqueductal stroke volume from phase-contrast MR imaging has been proposed for predicting shunt response in normal pressure hydrocephalus. However, this biomarker has remained controversial in use and has a lack of validation with invasive intracranial monitoring. We studied how aqueductal stroke volume compares with intracranial pressure scores in the presurgical work-up and clinical score, ventricular volume, and aqueduct area and assessed the patient's response to shunting. MATERIALS AND METHODS: Phase-contrast MR imaging was performed in 21 patients with probable idiopathic normal pressure hydrocephalus. Patients were selected for shunting on the basis of pathologically increased intracranial pressure pulsatility. Patients with shunts were offered a second MR imaging after 12 months. Ventricular volume and transverse aqueductal area were calculated, as well as clinical symptom score. RESULTS: No correlations between aqueductal stroke volume and preoperative scores of mean intracranial pressure or mean wave amplitudes were observed. Preoperative aqueductal stroke volume was not different between patients with shunts and conservatively treated patients (P = .69) but was correlated with ventricular volume (R = 0.60, P = .004) and aqueductal area (R = 0.58, P = .006) but not with the severity or duration of clinical symptoms. After shunting, aqueductal stroke volume (P = .006) and ventricular volume (P = .002) were reduced. A clinical improvement was seen in 16 of 17 patients who had shunts (94%). CONCLUSIONS: Aqueductal stroke volume does not reflect intracranial pressure pulsatility or symptom score, but rather aqueduct area and ventricular volume. The results do not support the use of aqueductal stroke volume for selecting patients for shunting.

Stimulation of 5-HT1 receptors in the spinal cord changes substance P-induced behaviour.

This study examined whether intrathecal (i.th.) injection of different 5-hydroxytryptamine (5-HT) receptor agonists modulated the behavioural response to substance P. Given intrathecally, substance P produces a behavioural syndrome consisting of biting of the lower parts of the abdomen and reciprocal hindlimb scratching, which may be indicative of nociceptive stimulation. The number of substance P-induced bites was reduced when counted 5 min after intrathecal injection of 5-HT, p-chloroamphetamine (PCA) which causes release of 5-HT from neuronal terminals, the non-selective 5-HT receptor agonist quipazine, the selective 5-HT1 receptor agonists (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT], 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969) and 1(m-chlorophenyl)piperazine (mCPP), but was unchanged by treatment with the 5-HT2/5-HT1C receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The number of scratches was significantly increased 5 min after injection of 5-HT and RU 24969. The results showed that intrathecal injection of 5-HT agonists, with a high affinity for the 5-HT1 receptor subtypes, reduced the total number of responses induced by intrathecal injection of substance P, whereas a 5-HT2/5-HT1C receptor agonist did not affect the behavioural response to the intrathecal injection of substance P.

Different role of 5-HT1A and 5-HT2 receptors in spinal cord in the control of nociceptive responsiveness.

The effects of the 5-hydroxytryptamine type-2 (5-HT2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)-8-OH-DPAT] on nociceptive responsiveness were compared in mice. Intrathecal administration of DOI (5-20 micrograms) produced a dose-dependent behavioural syndrome, consisting of biting or licking, directed towards the caudal part of the body and reciprocal hindlimb scratching. However, (+)-8-OH-DPAT (5-20 micrograms) did not produce the biting and scratching behaviour. The response to DOI (20 micrograms) was reversed by treatment with the substance P receptor antagonist, [D-Arg1, D-Trp7,9, Leu11]-SP (Spantide) (5 micrograms). The tail-flick reflex was markedly depressed 5-20 min after administration of (+)-8-OH-DPAT; DOI did not change the tail-flick reflex after 5 min but significantly inhibited the reflex response 10-20 min after injection. The data show that stimulation of 5-HT2 receptors, but not 5-HT1A receptors, induced a behavioural syndrome, which may reflect activation of nociceptive pathways. The tail-flick reflex was more markedly inhibited by stimulation of 5-HT1A than 5-HT2 receptors. Accordingly, 5-HT2 and 5-HT1A receptors seem to have a different function in the modulation of nociceptive responsiveness in the mouse.

Effects of serotonin receptor antagonists and agonists on the tail-flick response in mice involve altered tail-skin temperature.

Tail-flick latency and tail-skin temperature were measured in mice after administration of serotonin (5-HT) receptor antagonists (metergoline and metitepin) and agonists [5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)]. Metergoline (4 mg/kg) and metitepin (0.5 mg/kg) reduced the tail-flick latencies and increased the tail-skin temperatures, but the effect on the tail-flick latencies was non-significant when the effect of temperature was taken into account. Both 5-MeODMT (3 mg/kg) and 8-OH-DPAT (1 mg/kg) reduced the tail-skin temperature but only 5-MeODMT increased the tail-flick latencies. The effect of 5-MeODMT on tail-flick latencies was still highly significant when the effect of temperature was taken into account. The results show that the apparent hyperalgesia elicited by 5-HT receptor antagonists in the tail-flick test in the mouse is secondary to increased tail-skin temperature and not due to increased nociceptive sensitivity. The antinociceptive effect of 5-MeODMT in the tail-flick test can, however, not be explained by effects of temperature.

Test-dependent changes in nociception after administration of the putative serotonin antagonist metitepin in mice.

Intraperitoneal administration of the putative serotonin receptor antagonist metitepin (0.06-1.0 mg/kg) in mice induced dose-dependent antinociception in the increasing temperature hot-plate test and the formalin test, but elicited hyperalgesia in the tail-flick test. Reduced motor activity was observed after injection of the largest dose of metitepin, but did not influence the behavioural responses in the tests. Selective lesions of ascending serotonergic pathways induced by administration of the neurotoxin p-chloroamphetamine 5 and 6 days before testing (40 mg/kg each day) did not directly affect the responsiveness in any of the tests but enhanced the metitepin-induced antinociception in the hot-plate and formalin tests. The hyperalgesia in the tail-flick test was not affected by the lesions. The results suggest that metitepin may alter nociception in mice by exhibiting both agonist and antagonist properties on central serotonergic receptors.

The role of 5-HT1A and 5-HT1B receptors in spinal nociceptive transmission and in the modulation of NMDA induced behaviour.

The effects on nociception of intrathecal (i.th.) administration of selective 5-HT1A and 5-HT1B agonists were studied in rats. Nociception was evaluated using the tail-flick test with adjustments for tail-skin temperature, the increasing temperature hot-plate test and the scoring of biting and scratching behaviour after i.th. N-methyl-D-aspartate (NMDA). Activation of the spinal 5-HT1A receptor induced an antinociceptive effect in the increasing temperature hot-plate test and produced a dose dependent decrease in NMDA-receptor mediated behaviour. No significant change in nociception measured by either of the nociceptive tests was found after administration of the 5-HT1B agonist. These results support the hypothesis that spinal 5-HT1A receptor activation has an antinociceptive effect, and indicate a possible interaction between the serotonergic and glutaminergic transmitter systems.

Interactions between serotonin and substance P in the spinal regulation of nociception.

Interactions between 5-hydroxytryptamine (5-HT) and substance P (SP) in the mouse spinal cord were investigated using the tail-flick test and the behavioral response evoked by intrathecal (i.th.) SP or i.th. 5-HT. I.th. injection of 5-HT (20 micrograms) or the 5-HT1 receptor agonists (+)-8-hydroxy-2-(di-n-propylamino)tetralin ((+)-8-OH-DPAT) (20 micrograms) or 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969) (20 micrograms) markedly inhibited the tail-flick reflex. The effect of these compounds was reduced when SP (5 micrograms) was given i.th. 55 min, or 55 and 45 min before the agonists. The tail-flick latencies recorded 5 min before injection of a 5-HT receptor agonist were similar in animals treated with SP or vehicle. The changes in the tail-flick test were not due to changes in tail skin temperature since only minimal differences in the skin temperature were recorded between the groups injected with SP or vehicle. I.th. injection of SP (10 ng) or 5-HT (2 micrograms) produced a similar behavioral response consisting of biting, licking and scratching of the caudal part of the body, indicative of nociceptive stimulation. The responses both to i.th. SP and 5-HT were reduced after i.th. application of the SP receptor antagonist [D-Arg1,D-Trp7.9,Leu11]-SP (Spantide) (5 micrograms), as well as 5 min after i.th. injection of the 5-HT receptor antagonist metergoline (4 micrograms). The data may indicate functional interactions between SP and 5-HT in the mouse spinal cord, which may take place in neurons involved in the processing of nociception.