Repercusión de la pandemia COVID-19 en la actividad pediátrica en Atención Primaria / Impact of the COVID-19 pandemic on the pediatric activity in Primary Care

Introducción. La pandemia por COVID-19 ha supuesto un cambio en nuestras vidas y deseamos conocer su influencia en las consultas de pediatría en Atención Primaria. Pacientes y métodos. Estudio observacional retrospectivo de la actividad en un Centro de Salud urbano entre enero 2019 y marzo 2021. Se realiza aleatorización estratificada para elegir semana y día y se incluyen todos los pacientes. La información se extrae del programa Medora. Se recogen las variables: fecha de consulta, fecha de nacimiento, profesional, sexo, patología crónica, tipo y motivo de consulta, hospitalización reciente y afectación por COVID-19. Se realiza un análisis de regresión logística binaria y análisis de regresión de joinpoint. Resultados. La muestra es de 1.802 consultas. La tendencia de las tasas de consultas es estable de forma global y en la atención de enfermería, pero hay cambios estacionales en la atención de los pediatras. Durante la pandemia el tipo de consulta a la demanda/urgencia ha sido inferior que la programada (Odds Ratio = 0,19, IC al 95%: 0,1 a 0,3) y la atención telefónica/no presencial superior a la programada (Odds Ratio = 4,01: IC95% 2,3 a 6,95). El comportamiento de las consultas por tipo de patologías, consulta de revisión, vacunaciones o aspectos administrativos ha sido similar antes y durante la pandemia. Conclusión. El volumen de atenciones en nuestro Centro de Salud ha sido similar durante el periodo estudiado. La atención telefónica/no presencial ha sido cuatro veces superior a la consulta programada. Existen diferencias estacionales con descenso estival (AU)

Introduction. Our aim is to know the impact of the pandemic on pediatric activity in Primary Care.Patients and methods. Retrospective observational study of pediatric activity in an urban Health Center between January 2019 and March 2021. Stratified randomization is performed to choose the week and day. All patients are included. The information collected is extracted from the Medora program. Date of consultation, date of birth, professional, sex, chronic pathology, type and reason for consultation, recent hospitalization and involvement by COVID-19 are collected. Binary logistic regression analysis and regression analysis of joinpoint are performed.Results. The sample is made up of 1802 consultations. Trend in consultation rates is stable globally and in nursing care, but there are seasonal changes in pediatric care. During the pandemic, the demand/urgent consultation was lower than scheduled (Odds Ratio = 0.19, 95% CI 0.1 to 0.3) and telephone/non-face-to-face consultations were higher than scheduled (Odds Ratio = 4.01: 95% CI 2.3 to 6.95). The behavior of consultations by type of pathology, review consultation, vaccinations or administrative aspects has been similar before and during the pandemic.Conclusion. The number of consultations in our Health Center has been similar along the studied period. Telephone/non-face-to-face assistance has been four times higher thanscheduled consultation. There are seasonal differences in pediatric care with a summer decline (AU)

Percepción de los pediatras de Atención Primaria de su relación con la Pediatría Hospitalaria / Perception of the Primary Care pediatricians of their relationship with Hospital Pediatrics

Objetivo. El objetivo de este trabajo es conocer la percepción que tienen los pediatras de Atención Primaria (PAP) de Castilla y León de su relación con la Pediatría Hospitalaria. Población y métodos. Se realizó una encuesta entre los pediatras de Atención Primaria para conocer la relación entre niveles asistenciales en las 11 áreas sanitarias de la Comunidad. El cuestionario es anónimo y consta de 16 preguntas en dos bloques: 9 sobre “cómo es/cómo percibimos la relación entre los PAP y el hospital” (bloque 1) y 7 sobre “qué cosas son importantes para los PAP/qué se pide al hospital” (bloque 2). Se puntúa con una escala Likert de 1 (nada) a 5 (máximo). Resultados. Respondieron 134 pediatras (84% mujeres). El 64% tiene 15 años de experiencia en PAP. El 77% trabajan como pediatras de equipo, y el 64% en centros urbanos. El 43% tiene cupos de 800-999 pacientes. El 24% son tutores de apoyo MIR y el 24% colabora en la formación de estudiantes de Medicina. En el primer bloque de preguntas se observan medianas entre 2 y 4 de puntuación Likert, y en el segundo bloque los valores son más elevados (mediana 4). Encontramos diferencias significativas al comparar las respuestas por áreas sanitarias, en todas las preguntas del primer bloque y en la mayoría del segundo. Conclusión. La relación entre niveles es aceptable en su conjunto, con importantes diferencias entre áreas sanitarias (AU)

Objective. To know the perception that Primary Care pediatricians (PCP) of Castilla y Leon have about their relationship with hospital pediatricians. Population and methods. A survey was conducted among PCP to find out the relationship between healthcare levels in the 11 health areas of the Community. The questionnaire is anonymous and consists of 16 questions (two blocks): 9 about “how is/how we perceive the relationship between the PCP and the hospital” (first block) and 7 about “what is important for the PCP/what is asked to the hospital” (second block). It is scored on a Likert scale from 1 (not at all) to 5 (maximum). Results. 134 pediatricians answer (84% women). 64% have 15 years of experience as PCP. 77% work as team pediatrician, and 64% in urban settings. 43% attends 800-999 patients. 24% are support tutors and 24% are trainers of medical students. Medians between 2 and 4 of Likert scores are observed in the first block of questions, and values are higher (4) in the second one. We find significant differences when making comparisons by Health Areas in all the questions in the first block and in most of them in the second. Conclusión. The relationship between healthcare levels is acceptable as a whole with important differences among health areas (AU)

Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. I. Effects after oral administration.

BACKGROUND AND PURPOSE: Retinoic acid is an active metabolite of vitamin A involved in the modulation of the inflammatory and nociceptive responses. The aim of the present study was to analyze the properties of spinal cord neuronal responses of male Wistar rats treated with all-trans retinoic acid (ATRA) p.o. in the normal situation and under carrageenan-induced inflammation. We also studied the expression and distribution of cyclooxygenases (COX) in the spinal cord. EXPERIMENTAL APPROACH: Properties of spinal cord neurons were studied by means of the single motor unit technique. The expression of COX enzymes in the spinal cord was assessed by Western blot analysis and immunohistochemistry. KEY RESULTS: Intensity thresholds for mechanical and electrical stimulation (C-fibers) were significantly lower in animals treated with ATRA than vehicle, either in normal rats or in rats with inflammation. The size of cutaneous receptive fields was also larger in animals treated with ATRA in the normal and inflammatory conditions. The expression of COX-2 enzyme, but not COX-1, was significantly higher in animals treated with ATRA. COX-2 labeling was observed in dorsal horn cells and in ventral horn motoneurons. CONCLUSIONS AND IMPLICATIONS: In conclusion, the oral treatment with ATRA in rats induces a sensitization-like effect on spinal cord neuronal responses similar to that observed in animals with inflammation and might explain the enhancement of allodynia and hyperalgesia observed in previously published behavioral experiments. The mechanism of action involves an over-expression of COX-2, but not COX-1, in dorsal and ventral horn areas of the lumbar spinal cord.

Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration.

BACKGROUND AND PURPOSE: In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. EXPERIMENTAL APPROACH: The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. KEY RESULTS: The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. CONCLUSIONS AND IMPLICATIONS: In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord.

The oral administration of retinoic acid enhances nociceptive withdrawal reflexes in rats with soft-tissue inflammation.

OBJECTIVE AND DESIGN: To study the involvement of all-trans retinoic acid (ATRA) in the development and maintenance of inflammatory pain. SUBJECTS: Adult male Wistar rats and murine neuro2a and human SH-SY5Y neuroblastoma cells. TREATMENT: Soft-tissue inflammation was induced by the intraplantar administration of 100 microl of carrageenan lambda. The oral treatment with either ATRA or vehicle lasted for seven days and consisted in a dose of 15 mg/kg the first two days and a dose of 10 mg/kg the following five days. Neuroblastoma cells were incubated for 16 h with ATRA. METHODS: Rats were tested twice daily for intensity and evolution of withdrawal reflexes evoked by mechanical and thermal stimulation. The expression of COX enzymes was studied in spinal cords and neuroblastoma cells by western blot. RESULTS: The animals treated with ATRA showed a significantly more intense development of mechanical allodynia (p < 0.01), mechanical hyperalgesia (p < 0.01), thermal hyperalgesia (p < 0.001) and reduction of threshold for mechanical (29 +/- 4 vs. 60 +/- 6 mN, p < 0.001) and thermal stimulation (12 +/- 0.3 vs. 8.4 +/- 0.3 s, p < 0.001) than control animals. Recovery to mechanical baseline data was slower in animals treated with ATRA, the main difference was observed in the test carried out on day 2, p.m. In neuroblastoma cells incubated with ATRA, a concentration-dependent increase in the expression of COX-2 protein was observed. Changes in the expression of COX-1 enzyme were not clear. An increase in COX-2 expression in the lumbar spinal cord was also observed in animals treated with ATRA. CONCLUSIONS: A clear relationship between the oral administration of ATRA and an enhancement of the nociceptive withdrawal reflexes was observed in rats. This relationship was associated with an increment of the expression of the COX-2 enzyme.

Male Wistar rats show uniform wind-up responses in carrageenan-induced inflammation but not in the normal situation.

The technique of recording spinal cord withdrawal reflexes as single motor units (SMUs) does not require intense preparatory surgery and allows the study of the nociceptive system in physiological conditions. It has been used to show that the wind-up phenomenon depends on the level of excitability of spinal cord neurones, the integrity of the spinal cord and the parameters of the stimulation used. We have now used SMU recordings to assess whether wind-up is also an heterogeneous phenomenon depending on the muscle studied, and, if so, how the presence of hyperalgesia affects its generation. The experiments were performed in normal and carrageenan-induced inflammation in male Wistar rats anesthetized with alpha-chloralose. Wind-up was recorded in units from peroneus longus, tibialis anterior and extensor digitorum longus. The results showed that in normal animals, the curves of C-fibre mediated wind-up reached saturation at different times and the shape of the curves was different depending on the muscle studied and on the intensity of stimulation used. In inflammation, however, C-fibre mediated wind-up became very uniform in the muscles studied, with a similar shape and saturation point. A-fibre mediated wind-up was only observed in animals with inflammation and no differences were observed between muscles. We conclude that in the absence of preparatory surgery and inflammation, C-fibre wind-up is heterogeneous, and supports a modular organization of nociceptive spinal reflexes. In hyperalgesia, however, wind-up curves are similar in units from different muscles, confirming a loss of modular organization that also affects the generation of wind-up.

Cyclooxygenase-1 vs. cyclooxygenase-2 inhibitors in the induction of antinociception in rodent withdrawal reflexes.

Non-steroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) enzyme and so they are effective analgesic, antiinflammatory and antipyretic drugs. The discovery of COX-2 led to the search for new NSAIDs with a selective action over this isoenzyme. The experiments performed to date have shown either more, less or no different efficacy of new COX-2 selective NSAIDs when compared to the non-selective inhibitors, probably because the comparison has not been performed under similar conditions. We have therefore compared the analgesic activity of six NSAIDs with different selectivity for the COX isoenzymes. The experiments were performed using the recording of spinal cord nociceptive reflexes in anaesthetised rats and in awake mice. The non-selective COX inhibitors, such as dexketoprofen trometamol, were effective in reducing nociceptive responses both in normal and monoarthritic rats (ED50s: 0.31 and 3.97 micromol/kg, respectively), and in mice with paw inflammation (12.5 micromol/kg, p < 0.01). The COX-1 selective inhibitor SC-58560 showed efficacy in normal rats (ED50: 0.8 micromol/kg) and in mice with paw inflammation (15 micromol/kg, p < 0.05), but not in monoarthritic rats. The COX-2 selective inhibitors celecoxib (105 micromol/kg) and rofecoxib (128 micromol/kg) however, were not effective in any of the groups studied. We conclude that inhibition of both COX isoenzymes is needed to achieve an effective analgesia in inflammation.

Wind-up of spinal cord neurones and pain sensation: much ado about something?

Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning. Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors. However, most drugs capable of reducing the excitability of spinal cord neurones, including opioids and NSAIDs, can also reduce or even abolish wind-up. Thus, other theories involving synaptic efficacy, potassium channels, calcium channels, etc. have also been proposed for the generation of this phenomenon. Whatever the mechanisms involved in its generation, wind-up has been interpreted as a system for the amplification in the spinal cord of the nociceptive message that arrives from peripheral nociceptors connected to C-fibres. This probably reflects the physiological system activated in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses. On the other hand, wind-up, central sensitisation and hyperalgesia are not the same phenomena, although they may share common properties. Wind-up can be an important tool to study the processing of nociceptive information in the spinal cord, and the central effects of drugs that modulate the nociceptive system. This paper reviews the physiological and pharmacological data on wind-up of spinal cord neurones, and the perceptual correlates of wind-up in human subjects, in the context of its possible relation to the triggering of hyperalgesic states, and also the multiple factors which contribute to the generation of wind-up.

Antinociceptive effects of metamizol (dipyrone) in rat single motor units.

Metamizol has been considered as a peripherally acting non-steroidal antiinflammatory drug, though a central action is possible. The aim of the present study was to elucidate if metamizol induces antinociception in the single motor unit preparation, in normal rats versus rats with carrageenan-induced monoarthritis, and whether this action is produced at central and/or peripheral sites. Metamizol induced a potent antinociceptive effect in both groups of animals, though the effect on responses evoked by natural stimulation was stronger in hyperalgesic rats. Metamizol also depressed wind-up in a dose-dependent manner. We conclude that metamizol is a potent antinociceptive agent both in normal and hyperalgesic animals and that the effect was induced both at peripheral and central sites, at the level of the spinal cord.

The antinociceptive effect of the mu-opioid fentanyl is reduced in the presence of the alpha(2)-adrenergic antagonist idazoxan in inflammation.

Interactions between alpha(2)-adrenergic and mu-opioid systems play an important role in the modulation of hyperalgesic states. The antinociceptive effects of alpha(2)-adrenergic agonists and mu-opioids are potentiated when co-administered; however, attempts to induce cross reversal of the antinociceptive effects of alpha(2)-adrenergic and mu-opioid systems have produced contradictory results. We have studied the possible endogenous tonic control of the alpha(2)-adrenergic systems in the modulation of pain in inflammation, and the interactions between the two antinociceptive systems in rat spinal cord nociceptive reflexes activated by both natural and electrical stimulation. The facilitatory actions of the alpha(2)-adrenergic antagonist idazoxan were compared in control rats and in animals with carrageenan-induced paw inflammation. The antinociceptive effect of the mu-opioid fentanyl was tested alone and in the presence of idazoxan. In agreement with some previous observations, idazoxan i.v. produced no change in responses to natural and electrical stimulation in normal animals. In animals with inflammation, idazoxan only induced facilitation of responses evoked by noxious thermal stimulation but not by mechanical or electrical stimulation. Fentanyl reduced the responses to either stimuli with lower potency in the presence of idazoxan, but only in animals with inflammation. Its dose-response curve was shifted to the right between 1.8- and 3. 5-fold depending on the stimulus used. It is concluded that the increase of thermal responses by idazoxan in animals with inflammation is probably due to changes in the peripheral blood flow. Nevertheless, since an interaction with mu-opioids is clear in inflammation, endogenous alpha(2)-adrenergic systems play an important role in the modulation of the effectiveness of opioids during inflammation.

Response properties of hind limb single motor units in normal rats and after carrageenan-induced inflammation.

The properties of single motor units from hind limb muscles and the changes in situations of hyperalgesia are not known in detail. We have therefore characterized the properties of single motor units in normal Wistar male rats and in rats with carrageenan-induced inflammation, under alpha-chloralose anaesthesia. Units were studied from three different muscles: peroneus longus, tibialis anterior and extensor digitorum longus. The properties of single motor units were not homogeneous in the three muscles studied in normal animals, showing different sizes of cutaneous receptive fields, thresholds for natural and electrical stimulation, and encoding of responses at different intensities of stimulation. Intraplantar injections of carrageenan induced a significant inflammation of the paw and a change in spontaneous behaviour observed in open field experiments. After inflammation, the responses to cutaneous stimulation of the single motor units became more homogeneous. The threshold for mechanical stimulation was lower for peroneus longus and tibialis anterior but not for extensor digitorum longus units when compared to normal animals. The receptive fields were larger when mapped with a 500 mN von Frey hair but not when mapped using a threshold intensity hair. The threshold for thermal stimulation was lower after inflammation than in normal conditions in all cases, whereas the threshold for electrical stimulation was lower in tibialis anterior and extensor digitorum longus units. An enhancement of responses related to the increase of stimulus intensity was seen in normal animals in all muscles for mechanical and electrical stimuli (but not for thermal). After inflammation, a relationship between firing rate and intensity of stimulation was seen in all cases studied. The firing of single motor units showed over 50% adaptation in the normal condition and over 75% after inflammation when stimulated for 10 s at mechanical threshold intensity. After inflammation, the rate of adaptation was significantly lower when suprathreshold intensity was used for mechanical stimulation. No differences were seen in the adaptation of units to thermal stimulation. We conclude that, in situations of hyperalgesia due to inflammation, the threshold, encoding of stimulus intensity and adaptation of single motor units from different muscles changed, resulting in a narrower range of responses and a more homogeneous population of units.

The NSAID dexketoprofen trometamol is as potent as mu-opioids in the depression of wind-up and spinal cord nociceptive reflexes in normal rats.

The aim of this study was to examine the potency of the antinociceptive effects of the non-steroidal antiinflammatory drug (NSAID), Dexketoprofen Trometamol (the active enantiomer of ketoprofen) on spinal cord nociceptive reflexes. These effects were compared with those of the mu-opioid receptor agonist fentanyl in normal animals. The experiments were performed in male Wistar rats anaesthetised with alpha-chloralose. The nociceptive reflexes were recorded as single motor units in peripheral muscles, activated by mechanical and electrical stimulation. Both dexketoprofen and fentanyl inhibited responses evoked by mechanical and electrical stimulation with doses in the same nanomolar range (dexketoprofen ID50s: 100 and 762 nmol kg-1 and fentanyl: 40 and 51 nmol kg-1, respectively). Dexketoprofen and fentanyl also significantly inhibited wind-up. Since fentanyl has been shown to be some 1000 times more potent than morphine in this type of experiments, we conclude that dexketoprofen has central analgesic actions in normal animals and depresses nociceptive responses with a potency similar to that of mu-opioid agonists.

Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.

Stimulus intensity, cell excitation and the N-methyl-D-aspartate receptor component of sensory responses in the rat spinal cord in vivo.

The importance of receptors for N-methyl-D-aspartate in synaptic plasticity and in triggering long-term pronociceptive changes is explained by their voltage-dependence. This suggests that their contribution to acute nociceptive responses would be determined both by the magnitude of synaptic input and by the level of background excitation. We have now examined the role of N-methyl-D-aspartate receptors in acute nociceptive transmission in the spinal cord. Drugs selectively affecting activity mediated by these receptors were tested on responses of dorsal horn neurons to noxious stimuli of different intensities and at different levels of ongoing spike discharge. The drugs used were the N-methyl-D-aspartate receptor channel blocker ketamine; the competitive antagonists, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP) and D-2-amino-5-phosphonopentanoic acid (D-AP5), and the positive modulator thyrotropin-releasing hormone. The activity of dorsal horn wide dynamic range neurons was recorded extracellularly in alpha-chloralose-anaesthetized spinalized rats. Their responses to noxious stimuli (pinch, heat and electrical) were monitored in parallel with responses to iontophoretic N-methyl-D-aspartate and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA). Drugs were given i.v. or (D-AP5) iontophoretically. At doses that selectively inhibited responses to exogenous N-methyl-D-aspartate, ketamine (4 or 8, mean 5 mg/kg i.v.) reduced the nociceptive responses of the majority of the cells in deep dorsal horn. Ketamine also reduced wind-up of the responses to repetitive electrical stimulation. Ketamine (4 or 8 mg/kg). D-CPP (2 mg/kg), D-AP5 (iontophoretically) and thyrotrophin-releasing hormone (1 mg/kg) were tested on different magnitude nociceptive responses evoked by alternating intensities of noxious heat or pinch. In percentage terms, the less vigorous responses were affected by all four drugs as much as or more than the more vigorous responses. When background activity of neurones was enhanced by continuous activation of C-fibres with cutaneous application of mustard oil, ketamine was less effective against superimposed noxious pinch responses. Ongoing background activity was affected in parallel with evoked responses. When background discharge of the cells was maintained at a stable level with continuous ejection of kainate, neither the N-methyl-D-aspartate antagonists nor thyrotrophin-relasing hormone affected the responses to noxious pinch or heat, although responses to exogenous N-methyl-D-aspartate were still blocked. The wind-up of the electrical responses was, however, reduced by ketamine irrespective of the level of background activity. The results indicate that under these conditions in vivo, N-methyl-D-aspartate receptors mediate ongoing low-frequency background activity rather than phasic high-frequency nociceptive responses. The effects of N-methyl-D-aspartate antagonists and positive modulators on nociceptive responses are evidently indirect, being secondary to changes in background synaptic excitation. These results cannot be explained simply in relation to the voltage-dependence of N-methyl-D-aspartate receptor-mediated activity; other factors, such as modulation by neuropeptides, must be involved.

Analgesic activity of the novel COX-2 preferring NSAID, meloxicam in mono-arthritic rats: central and peripheral components.

OBJECTIVE AND DESIGN: To study the characteristics and site of the analgesic action of meloxicam. SUBJECTS: Adult female Wistar rats. TREATMENT: Monoarthritis was induced (for behavioural studies) by injection of complete Freund's adjuvant into the ankle. Meloxicam was given for 5 days (0.1-4 mg/kg/ day i.p.). Inflammation of the knee or paw (for electrophysiology) was induced with carrageenan. Meloxicam was given i.v. (4-64 mg/kg). METHODS: Rats were tested daily for joint hyperalgesia, and hindlimb posture (behaviour). At post-mortem, joint stiffness, oedema and gastric lesions were assessed. In anaesthetised rats, nociceptive reflex responses to stimulation of the paw were compared (electrophysiology). Statistics were performed using one-way analysis of variance. RESULTS: Meloxicam reduced swelling and stiffness of the inflamed joint, joint hyperalgesia (ID50 = 0.4 +/- 0.4 mg/kg/ day) and spontaneous pain-related behaviour. It also inhibited peripherally mediated reflex responses to stimulation of inflamed tissue (ID50 = 7.6 +/- 0.8 mg/kg.i.v.) without affecting centrally mediated reflexes. CONCLUSIONS: Systemic meloxicam produces analgesia largely via peripheral mechanisms. The rapidity of its actions indicates a direct effect on sensitised nociceptors.

Cutaneous responsiveness of rat single motor units activated by natural stimulation.

Recordings of withdrawal reflexes have been used extensively to study sensory-motor integration and processing of nociceptive information in the spinal cord. We describe here a new technique for the manufacture of improved EMG electrodes that permit the characterisation of the physiological properties of single motor units as well as the easy location of the muscles studied. Individual motor units from three rat hind-limb muscles: peroneus longus, tibialis cranialis and extensor digitorum longus, were activated by thermal and mechanical stimulation applied to their cutaneous receptive fields, which were located mainly on the 4th and 5th toes. Thresholds for thermal and mechanical (Von Frey hairs) stimulation were similar in the three muscles studied, with a value of 44 +/- 1 degrees C and 100 mN (median), respectively. However, when a mechanical pincher with a stimulus area of 14 mm2 was used, the values seen were similar for peroneus longus and tibialis cranialis (342 +/- 23 and 330 +/- 71 mN, respectively, mean +/- S.E.M.) but lower for extensor digitorum longus (220 +/- 37 mN, mean +/- S.E.M.). The firing rate of the single motor units was similar for all types of stimulation at threshold intensity, and showed a linear relationship with stimulus intensity, except for units of the tibialis cranialis, which showed a greater degree of adaptation.

Central and peripheral actions of the NSAID ketoprofen on spinal cord nociceptive reflexes.

Ketoprofen is a non-steroidal antiinflammatory drug (NSAID) which provides effective analgesia in situations of pain provoked by tissue inflammation. However, the location of its analgesic effects, (peripheral tissues versus central nervous system), have not been clearly identified and separated. In the present study the effectiveness of ketoprofen was examined in two different types of experiments: (i) Open field behavioural tests in conscious rats, and (ii) spinal cord nociceptive reflexes (single motor units) activated by electrical and thermal stimulation in chloralose anaesthetised rats. The experiments were performed in rats with carrageenan-induced inflammation of one hindpaw, or of one knee joint. The administration of ketoprofen significantly inhibited the reduction of exploratory movements caused by inflammation in open field experiments. Ketoprofen was also effective in depressing reflex activity evoked by electrical and noxious thermal stimulation of the skin, either in inflamed tissue or in normal tissue of monoarthritic animals. It was also effective in the reduction of reflex wind-up; a phenomenon in which the activity of spinal cord neurones increases progressively with high frequency electrical stimulation. We therefore conclude that ketoprofen has central as well as peripheral analgesic activity.

Reversal by naloxone of the spinal antinociceptive actions of a systemically-administered NSAID.

1. Possible interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and endogenous opioids were examined in electrophysiological experiments in alpha-chloralose anaesthetized spinalized rats without or with carrageenan-induced acute inflammation of one hindpaw. Spinal reflex responses, monitored as single motor unit discharges, were elicited by noxious pinch and electrical stimuli. 2. The mu-opioid agonist, fentanyl, was an effective depressant of reflexes under all conditions (ED50 6-14 micrograms kg-1, i.v.). In rats without peripheral inflammation the NSAID, flunixin, a niflumic acid derivative, had only a small effect that was not dose-dependent. However, in animals with unilateral inflammation, flunixin reduced spinal reflexes evoked both by noxious pinch stimuli (that activate peripheral nociceptors; ID50 4 mg kg-1, i.v.) and by electrical stimuli (that bypass nociceptor endings; ID50 6.5- 11 mg kg-1, i.v.), indicating that it has a central site of action at doses comparable to those used clinically. 3. The opioid antagonist, naloxone (1 mg kg-1, i.v.), reversed all actions of fentanyl. It did not reverse the small effects that flunixin had in rats without inflammation, showing that the NSAID is not a direct opioid agonist. In rats with carrageenan-induced inflammation of the hindpaw, however, naloxone fully reversed or prevented the antinociception by flunixin, but not that by the alpha 2-adrenoceptor agonist, medetomidine. 4. We conclude that under conditions of peripheral inflammation and the resultant central changes, the NSAID, flunixin, has antinociceptive actions that are mediated by endogenous opioids acting within the spinal cord.

Supraspinal influences on the facilitation of rat nociceptive reflexes induced by carrageenan monoarthritis.

During hyperalgesia there is an enhancement of wind-up and the appearance of a novel wind-up of the A-fibre-mediated responses. We have examined if these phenomena are influenced by supraspinal mechanisms by analysing single motor unit activity in control and arthritic rats, either intact or acutely spinalised. Enhancement of the C-fibre wind-up and the novel A-fibre wind-up were only observed in the intact arthritic animals. We conclude that C-fibre wind-up is a spinal phenomenon, whereas the enhancement of the C-fibre wind-up and the novel A-fibre wind-up during arthritis depend also on supraspinal influences.

Changes in nociceptive reflex facilitation during carrageenan-induced arthritis.

Facilitation of neuronal responses induced by repetitive electrical stimulation of C-fibres (wind-up) is thought to be a substrate of hyperalgesia. There is little information on how these responses are in turn modified during hyperalgesia, and the extent to which hyperalgesic states also induce a facilitation of the neuronal responses mediated by A-fibres. The current study was undertaken in order to evaluate the effects of peripheral inflammation and stimulus presentation on the facilitation of nociceptive reflexes. Flexor reflexes, recorded as single motor units, were evoked in rats by cycles of low and high frequency electrical stimulation with pulse durations of 0.2, 0.5 and 2 ms. Responses were studied in control and inflammatory conditions, using the carrageenan-induced mono-arthritis model. The results show that the facilitation of late (C-fibre mediated) responses was proportional to the pulse duration of stimulation, as well as to the stimulation frequency. Facilitation was always higher when animals were subjected to inflammation. In inflammatory conditions, facilitation of reflexes was observed not only for late (C-fibre mediated) but also for early (A-fibre mediated) reflex responses. However, the facilitation of these early responses was not proportional to the intensity of stimulation. Thus, in arthritic animals, late (C-fibre mediated) flexion reflexes elicited from the skin, are facilitated and early (A-fibre mediated) reflexes are not only facilitated but, in addition, show a novel wind-up phenomenon.