Papers by Moshe Jakubowski
Neurology, 2005
The gradual development of cutaneous allodynia during the course of a migraine attack is commonly... more The gradual development of cutaneous allodynia during the course of a migraine attack is commonly detected by quantitative sensory testing (QST) in migraineurs seeking secondary and tertiary medical help. In this study, the authors developed a questionnaire that tested the recollection of the patients on their skin sensitivity during past migraine attacks. The authors devised a series of questions regarding skin sensitivity during migraine and posed them to 89 migraineurs when they were free of migraine (Visit 1). To validate their recollections, the authors determined the patients' pain thresholds to mechanical and thermal skin stimuli in the absence of migraine (Visit 1) and during an attack (Visit 2), using QST. Whereas 75.3% of the patients testified to at least one type of skin hypersensitivity during migraine, 24.7% were unaware of any abnormal skin sensitivity. The questionnaire correctly identified 84.8% of the 66 patients classified as allodynic by QST and mislabeled the remaining 15.2% as nonallodynic (false negatives). Among the 23 patients classified as nonallodynic by QST, 47.8% were mislabeled as allodynic using the questionnaire (false positives). Among the total number of 89 patients studied, the questionnaire produced 62.9% true positives and 13.5% true negatives (= 76.4% correct labeling) vs 12.4% false positives and 11.2% false negatives (= 23.6% mislabeling). The reliability of the questionnaire as a diagnostic tool of allodynia varies with the proportion of allodynic patients in a given clinic. The major source of variability is the misconception of nonallodynic patients that their skin is hypersensitive during migraine.
Molecular Brain Research, 1996
We have characterized the nuclear and cytoplasmic RNA transcripts derived from the gonadotropin r... more We have characterized the nuclear and cytoplasmic RNA transcripts derived from the gonadotropin releasing hormone (GnRH) gene in a mouse hypothalamic neuronal GT1 cell line. Analyses of nuclear GnRH RNA precursors present in the GT1 cells by RNase protection assay show that there is no particular order of intron excision, suggesting the existence of multiple processing pathways. A similar pattern is observed in mouse preoptic area-anterior hypothalamus (POA-AH). In GT1 cells, approximately 5% of the total GnRH RNA transcripts are found in the nucleus. In contrast, in the POA-AH of mice, nuclear transcripts comprise 40% of the total GnRH transcripts. Thus the GT1 cells, while similar in overall GnRH RNA processing to mouse hypothalamic GnRH neurons, do not exhibit the high abundance of nuclear GnRH RNA transcripts seen in the rodent GnRH neuron in vivo. Quantitative analysis of the nuclear RNA species shows that the GnRH primary transcript comprises more than 90% of the total nuclear GnRH mRNA precursors in both GT1 cells and mouse POA-AH and thus GnRH processing intermediates account for fewer than 10% of these precursors. Using these probes, we have examined changes in GnRH primary transcript expression in GT1-7 cells. In the presence of RNA synthesis inhibitors, the half-life of the GnRH primary transcript was found to be quite short, approximately 18 min, suggesting that the level of primary transcript would reflect levels of GnRH gene transcription. When GT1-7 cells are treated with the phorbol ester PMA (phorbol, 12-myristate, 13-acetate) for 1 h, GnRH primary transcript levels decrease by approximately 70%. Supporting the hypothesis that GnRH primary transcript is a good indicator of GnRH gene transcription is the finding that 1 h of PMA treatment results in a similar (approximately 50%) decrease in GnRH gene transcription, as assayed by nuclear run-on assay. Our observation that GT1 cells resemble mouse hypothalamic GnRH neurons in their pattern of intron excision and in the ratio of primary transcript to other nuclear transcripts emphasizes the utility of these cells for studying the regulation of GnRH gene expression in this immortalized hypothalamic cell line.
Headache Currents, 2004
Keywords:allodynia;trigeminovascular;triptan;aura;5 HT1B/1D;hypersensitivityallodynia;trigeminova... more Keywords:allodynia;trigeminovascular;triptan;aura;5 HT1B/1D;hypersensitivityallodynia;trigeminovascular;triptan;aura;5 HT1B/1D;hypersensitivity
Neuroendocrinology, 1988
Frontal, dorsal, or sham deafferentations were placed at various locations within the hypothalamu... more Frontal, dorsal, or sham deafferentations were placed at various locations within the hypothalamus in order to study the neural pathways involved in pseudopregnancy (PSP), estrous cyclicity, and prolactin (PRL) secretion in the rat. Dorsal or sham transections did not interfere with PSP or estrous cyclicity. Frontal cuts placed on day 3-4 of PSP between the posterior border of the optic chiasm and the anterior tip of the mediobasal hypothalamus (MBH) led to interruption of diestrus within 3-5 days. With frontal cuts placed more caudally in the MBH, and with frontal cuts placed rostrally at the anterochiasmatic area, the duration of PSP was within normal range. Irrespective of their effects on PSP, anterochiasmatic and retrochiasmatic cuts were associated with onset of persistent estrus, and MBH transections resulted in either persistent estrus in some rats or regular estrous cycles in the others. In deafferentated rats that showed persistent estrus, the basal plasma concentrations of PRL measured 3-4 weeks after ovariectomy were 2- to 3-fold higher than in deafferentated and sham-deafferentated animals that were cyclic before ovariectomy. Electrical vaginocervical stimulation induced secretion of nocturnal PRL surges in long-term ovariectomized rats with dorsal or sham transections, but not in those bearing frontal cuts, regardless of the neuroanatomical location of the frontal cut. These results suggest that (1) impulses generated at the uterine cervix must reach the medial preoptic area, a putative 'anti-surge center', and proceed from there to the MBH, in order to allow initiation of nocturnal PRL release.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Comparative Neurology, 2009
Migraine sufferers frequently testify that their headache feels as if the calvarial bones are def... more Migraine sufferers frequently testify that their headache feels as if the calvarial bones are deformed, crushed, or broken (Jakubowski et al. [2006] Pain 125:286–295). This has lead us to postulate that the calvarial bones are supplied by sensory fibers. We studied sensory innervation of the calvaria in coronal and horizontal sections of whole-head preparations of postnatal and adult mice, via immunostaining of peripherin (a marker of thinly myelinated and unmyelinated fibers) or calcitonin gene-related peptide (CGRP; a marker more typical of unmyelinated nerve fibers). In pups, we observed nerve bundles coursing between the galea aponeurotica and the periosteum, between the periosteum and the bone, and between the bone and the meninges; as well as fibers that run inside the diploë in different orientations. Some dural fibers issued collateral branches to the pia at the frontal part of the brain. In the adult calvaria, the highest concentration of peripherin- and CGRP-labeled fibers was found in sutures, where they appeared to emerge from the dura. Labeled fibers were also observed in emissary canals, bone marrow, and periosteum. In contrast to the case in pups, no labeled fibers were found in the diploë of the adult calvaria. Meningeal nerves that infiltrate the periosteum through the calvarial sutures may be positioned to mediate migraine headache triggered by pathophysiology of extracranial tissues, such as muscle tenderness and mild trauma to the skull. In view of the concentration of sensory fibers in the sutures, it may be useful to avoid drilling the sutures in patients undergoing craniotomies for a variety of neurosurgical procedures. J. Comp. Neurol. 515:331–348, 2009. © 2009 Wiley-Liss, Inc.
Journal of Comparative Psychology, 1985
The responses toward young shown by males and nulliparous females differed substantially between ... more The responses toward young shown by males and nulliparous females differed substantially between two outbred stocks of laboratory rats. Sprague-Dawley females showed maternal behavior either spontaneously (35% of the naive rats) or through concaveation (92% of the initially neutral virgins). Of the Wistar females, however, only 10% showed maternal behavior spontaneously, and only 29% of the neutral virgins came to behave maternally during 15 days of concaveation. Prepubertal cohabitation with lactating rats did not facilitate maternal responsiveness in adulthood in the Wistar virgin females. Of the Sprague-Dawley males, 50% showed paternal behavior spontaneously, and only 4% killed the young. Among the Wistar males, however, only 4% showed paternal behavior spontaneously, and 76% killed pups. Such profound differences between outbred stocks of rats may be a source of discrepancies between the results of studies dealing with the induction of parental behavior in nonlactating rats.
Neuroendocrinology, 1986
The role played by the medial preoptic area-anterior hypothalamus (MPOA-AH) in the regulation of ... more The role played by the medial preoptic area-anterior hypothalamus (MPOA-AH) in the regulation of reproductive function of the female rat was examined in the first part of the present study. Extensive bilateral lesions placed in different locations of the MPOA-AH continuum resulted in three different patterns of vaginal smears. Lesions located most rostrally and dorsally, sparing the suprachiasmatic nuclei (SCN), resulted in series of successive pseudopregnancies. Lesions located more caudally and ventrally, still sparing the SCN, eventuated in regular oestrus cycles with only occasional pseudopregnancies. MPOA-AH lesions encroaching upon the SCN were associated with persistent vaginal cornification. MPOA-AH-lesioned females exhibiting repeated pseudopregnancies were capable of mating, conceiving, and giving birth. Parturition in these females was uniformly delayed by 1 day and was associated with a variable incidence of stillbirth, cannibalism of newborn, or incomplete placentophagy. As a rule, MPOA-lesioned mothers did not retrieve pups but they did show crouching behaviour and some of them even secreted milk. Thus, while the MPOA subserves in the regulation of oestrous cyclicity and maternal behaviour, it appears to play no essential role in mating behaviour or in ovarian function during pregnancy and lactation. The pattern of prolactin secretion in MPOA-AH-lesioned male and female rats was evaluated in the second part of this study. Both intact and orchidectomized males were incapable of generating nocturnal prolactin surges following extensive bilateral ablation of the MPOA-AH. On the other hand, 6 out of 9 ovariectomized MPOA-AH-lesioned females exhibited spontaneous nightly surges of prolactin. The absence of the surges in the remaining 3 females was associated with invasion of the lesion into the SCN and/or structures rostral to the MPOA. During the light period, prolactin levels remained within the basal range in all lesioned females, irrespective of the presence or the absence of the nocturnal surge. These lesioned ovariectomized females, in contrast to nonlesioned females, were incapable of producing a diurnal (afternoon) surge of prolactin in response to administration of oestrogen, though their basal prolactin levels were much higher than the levels seen in oestrogen-treated, nonlesioned castrated males. These results support the view that the MPOA is inhibitory to the nocturnal prolactin surge while stimulatory to the diurnal surge. The results also suggest that the male rat is functionally devoid of both a 'diurnal-surge centre' residing in the MPOA, and a 'nocturnal-surge centre' located outside the MPOA.
European Journal of Neuroscience, 2008
Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutane... more Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non-selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non-selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single-unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non-selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of Aδ- and C-units and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) onto the dural receptive field of Aδ- and C-unit nociceptors also reversed the neuronal hyper-responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache.
Revue Neurologique, 2005
Migraine is a neurological disorder which leads to recurring, unilateral, throbbing headache, ass... more Migraine is a neurological disorder which leads to recurring, unilateral, throbbing headache, associated with variable incidence of aura (i.e., visual, sensory and motor function disturbances), nausea and vomiting, photophobia and phonophobia, fatigue, and enhanced irritability. We have recently shown that migraine headache is also associated with high incidence of ipsilateral cutaneous allodynia, particularly in periorbital and temporal skin areas. Patients who experience cutaneous allodynia during migraine feel that their skin hurts in response to otherwise innocuous activities such as combing, shaving, taking a shower, or wearing glasses or earrings. Here, we present evidence to support the view that the development of throbbing in the initial phase of migraine is mediated by sensitization of peripheral trigeminovascular neurons that innervate the meninges, and that the development and maintenance of cutaneous allodynia later in the attack is propelled by sensitization of central trigeminovascular neurons which receive converging sensory input from the meninges as well as from the scalp and facial skin. We also present evidence that the development of cutaneous allodynia during migraine is detrimental to termination of acute migraine attacks using triptans (5HT1B/1D receptor agonist).La migraine est une affection neurologique caractérisée par des crises de céphalées pulsatiles unilatérales diversement associées à des nausées, vomissements, phonophotophobie, irritabilité et à une aura neurologique (visuelle, sensitive ou motrice). Nous avons récemment montré que les céphalées migraineuses étaient également fréquemment associées à une allodynie homolatérale, notamment dans les régions péri-orbitaires et temporales. Les patients qui ont une telle allodynie ressentent comme douloureuses des stimulations qui ne le sont habituellement pas, telles que se peigner, se raser, prendre une douche, porter des lunettes ou des boucles d’oreille. Nous montrons ici que le développement de la phase initiale pulsatile de la crise de migraine est lié à une « sensibilisation » des neurones trigémino-vasculaires périphériques qui innervent la méninge et que le développement et le maintien de l’allodynie cutanée durant le reste de la crise sont dus à la sensibilisation des neurones trigémino-vasculaires centraux qui reçoivent des afférences sensitives convergentes venant à la fois des méninges et de la peau du visage et du crâne. Nous montrons également que le développement de cette allodynie cutanée pendant la crise de migraine contrecarre l’efficacité des triptans (agonistes des récepteurs 5HT 1B/1D) dans le traitement de la crise.
Neuroscience, 2007
We have previously observed that migraine attacks impervious to triptan therapy were readily term... more We have previously observed that migraine attacks impervious to triptan therapy were readily terminated by subsequent i.v. administration of the non-steroidal anti-inflammatory drug (NSAID) ketorolac. Since such attacks were associated with periorbital allodynia—a symptom of central sensitization—we examined whether infusion of the NSAID naproxen can block sensitization of central trigeminovascular neurons in the medullary dorsal horn, using in vivo single-unit recording in the rat. Topical exposure of the cerebral dura to inflammatory soup (IS) for 5 min resulted in a short-term burst of activity (<8 min) and a long-lasting (>120 min) neuronal hyper-responsiveness to stimulation of the dura and periorbital skin (group 1). Infusion of naproxen (1 mg/kg) 2 h after IS (group 1) brought all measures of neuronal responsiveness back to the baseline values recorded prior to IS, and depressed ongoing spontaneous activity well below baseline. When given preemptively 1 h before IS (group 2), naproxen blocked the short-term burst of activity and every long-term measure of neuronal hyper-responsiveness that was studied in the central neurons. The same preemptive treatment, however, failed to block IS-induced short-term bursts of activity in C-unit meningeal nociceptors (group 3). The results suggest that parenteral administration of naproxen, unlike triptan therapy, can exert direct inhibition over central trigeminovascular neurons in the dorsal horn. Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department.
Handbook of Clinical Neurology, 2010
The majority of migraineurs seeking secondary or tertiary medical care experience throbbing pain ... more The majority of migraineurs seeking secondary or tertiary medical care experience throbbing pain and cutaneous allodynia during the course of migraine. Underlying the origin of these symptoms are peripheral and central trigeminovascular neurons, whose cell bodies are located in the trigeminal ganglion and the spinal dorsal horn, respectively. The development of throbbing in the initial phase of migraine is mediated by sensitization of peripheral trigeminovascular neurons, whereas the development of cutaneous allodynia later in the attack is propelled by sensitization of central trigeminovascular neurons which, unfortunately, are not equipped to respond to triptans directly. Triptans appear to act presynaptically in the dorsal horn, such as to inhibit signal transmission from peripheral to central trigeminovascular neurons. Reining in the central neurons using triptan treatment is possible as long as their excitability remains driven by incoming signals from the meninges, but not after they develop autonomous activity. Accordingly, attacks with allodynia can be effectively terminated, provided that the patient vigilantly resorts to triptan therapy before or soon after the onset of allodynia, but not after allodynia has become firmly established. On the other hand, allodynic patients who missed the critical window for effective triptan therapy can still be rendered pain-free using an intravenous infusion of non-steroidal anti-inflammatory drugs.
Proceedings of The National Academy of Sciences, 2001
A common complaint among pain patients is that they lose their appetite. These accounts are anecd... more A common complaint among pain patients is that they lose their appetite. These accounts are anecdotal, however, and the neural mechanism underlying pain-induced loss of appetite remains unknown. In this study, we documented the occurrence of appetite loss in patients under migraine attack and investigated the neuronal substrate of pain-induced anorexia in our animal model of intracranial pain. We found that loss of appetite during the migraine attack in humans coincided strongly with the onset and duration of the head pain in 32͞39 cases, and that brief noxious stimulation of the dura in conscious rats produced a transient suppression of food intake. Mapping of neuronal activation in the rat showed that noxious dural stimulation induced a 3-to 4-fold increase in the number of Fos-positive neurons in medullary dorsal horn areas that process nociceptive signals (laminae I, V) and in parabrachial and hypothalamic neurons positioned to suppress feeding behavior. In the parabrachial area, activated neurons were localized in the superior-lateral subnucleus, and 40% of them expressed the mRNA encoding the anorectic neuropeptide cholecystokinin. In the hypothalamus, activated Fos-positive neurons were found in the dorsomedial area of the ventromedial nucleus, and 76% of them expressed the mRNA for cholecystokinin type-B receptor. Based on these findings, we suggest that at least one of several groups of hypothalamic neurons that normally inhibit appetite in response to metabolic cues is positioned to mediate the suppression of food intake by pain signals. www.pnas.org͞cgi͞doi͞10.1073͞pnas.171616898
Journal of Comparative Neurology, 2005
Migraine headache is triggered by and associated with a variety of hormonal, emotional, nutrition... more Migraine headache is triggered by and associated with a variety of hormonal, emotional, nutritional, and physiological changes. The perception of migraine headache is formed when nociceptive signals originating in the meninges are conveyed to the somatosensory cortex through the trigeminal ganglion, medullary dorsal horn, and thalamus. Is there a common descending pathway accounting for the activation of meningeal nociceptors by different migraine triggers? We propose that different migraine triggers activate a wide variety of brain areas that impinge on parasympathetic neurons innervating the meninges. According to this hypothesis, migraine triggers such as perfume, stress, or awakening activate multiple hypothalamic, limbic, and cortical areas, all of which contain neurons that project to the preganglionic parasympathetic neurons in the superior salivatory nucleus (SSN). The SSN, in turn, activates postganglionic parasympathetic neurons in the sphenopalatine ganglion, resulting in vasodilation and local release of inflammatory molecules that activate meningeal nociceptors. Are there ascending pathways through which the trigeminovascular system can induce the wide variety of migraine symptoms? We propose that trigeminovascular projections from the medullary dorsal horn to selective areas in the midbrain, hypothalamus, amygdala, and basal forebrain are functionally positioned to produce migraine symptoms such as irritability, loss of appetite, fatigue, depression, or the quest for solitude. Bidirectional trafficking by which the trigeminovascular system can activate the same brain areas that have triggered its own activity in the first place provides an attractive network of perpetual feedback that drives a migraine attack for many hours and even days. J. Comp. Neurol. 493:9–14, 2005. © 2005 Wiley-Liss, Inc.
Proceedings of The National Academy of Sciences, 2004
Triptans are 5HT1B/1D receptor agonists commonly prescribed for migraine headache. Although origi... more Triptans are 5HT1B/1D receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.
Annals of Neurology, 2004
We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during m... more We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental to the anti-migraine action of the 5HTIB/ID receptor agonists known is triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to received convergent inputs from the dura and facial skin. The effects of sumatriptan (300 μg/kg i.v.) on central sensitization induced by topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 h after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment; neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. On the other hand, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan. Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be induced 2 h after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than central trigeminovascular neurons. Ann Neurol 2004;55:000–000
Pain, 2007
Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonge... more Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.
Physiology & Behavior, 1985
JAKUBOWSKI, M. AND J. TERKEL. Transition from pup killing to parental behavior in male and virgin... more JAKUBOWSKI, M. AND J. TERKEL. Transition from pup killing to parental behavior in male and virgin female albino rats. PHYSlOL BEHAV 34(5) 683-686, 1985.--In the first part of this study, the effect of habituation to pups was examined in virgin female and male Spragne-Dawley rats that committed infanticide in a screening test. With repeated exposure to test pups (5-10 days old), the rats ceased to commit infanticide and came to behave parentally. Preexposure to inaccessible pups (confined inside wire-mesh baskets) did not accelerate the rate of disappearance of infanticide during subsequent contact with young, which suggests that pup killing is not a neophobic response to the novelty of young. In the second part of the study, three groups of infanticidal male Wistar rats were mated and tested for their responses towards unrelated pups after different intervals of cohabitation with their mates. The males continued to commit infanticide at the time that their mates were at midpregnancy or 24 hr before parturition, but males that cohabited with their mates till day 9 postpartum no longer attacked the young. Thus, the mother rat, presumably by means of postpartum aggression, renders her mate noninfanticidal, thereby reducing the likelihood of her offspring being harmed when she is away from the nest.
Pain, 2007
Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonge... more Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell -induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.
Pain, 2006
Migraine headache is routinely managed using medications that abort attacks as they occur. An alt... more Migraine headache is routinely managed using medications that abort attacks as they occur. An alternative approach to migraine management is based on prophylactic medications that reduce attack frequency. One approach has been based on local intramuscular injections of Botulinum Toxin Type A (BTX-A). Here, we explored for neurological markers that might distinguish migraine patients who benefit from BTX-A treatment (100 units divided into 21 injections sites across pericranial and neck muscles). Responders and non-responders to BTX-A treatment were compared prospectively (n=27) and retrospectively (n=36) for a host of neurological symptoms associated with their migraine. Data pooled from all 63 patients are summarized below. The number of migraine days per month dropped from 16.0±1.7 before BTX-A to 0.8±0.3 after BTX-A (down 95.3±1.0%) in 39 responders, and remained unchanged (11.3±1.9 vs. 11.7±1.8) in 24 non-responders. The prevalence of aura, photophobia, phonophobia, osmophobia, nausea, and throbbing were similar between responders and non-responders. However, the two groups offered different accounts of their pain. Among nonresponders, 92% described a buildup of pressure inside their head (exploding headache). Among responders, 74% perceived their head to be crushed, clamped or stubbed by external forces (imploding headache), and 13% attested to an eye-popping pain (ocular headache). The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the prevailing view that migraine pain is mediated by intracranial innervation. The amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain involve extracranial innervation as well. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
Pain, 2005
Consistent with previous accounts, some of the patients visiting our pain clinic during the cours... more Consistent with previous accounts, some of the patients visiting our pain clinic during the course of a migraine attack have indicatedwithout solicitation-that sumatriptan injection initially intensified their headache before they were able to appreciate any pain relief. In this study, those patients who came forward complaining about pain exacerbation were asked to rate their headache intensity every 5 min. Within 5-15 min of sumatriptan injection, 17 of the 31 patients studied (55%) reported that their migraine pain intensified for 10-15 min before they started to notice any pain relief. Similar pattern of pain exacerbation was also observed in migraine attacks treated with oral formulation of almotriptan, eletriptan, rizatriptan, and zolmitriptan. To investigate the possible mechanism underlying this transient exacerbation of pain, we examined whether intravenous administration of sumatriptan can alter the response properties of C-and Ad-meningeal nociceptors in the rat. Five to twenty minutes after intravenous administration of 300 mg/kg sumatriptan, 8/10 C-units and 2/8 Ad-units increased their firing rate, and 6/10 C-units and 7/8 Ad-units developed mechanical hyper-responsiveness to dural indentation. The minimal effective dose for activation and sensitization of meningeal nociceptors by sumatriptan was 3 mg/kg, suggesting that relatively low levels of triptans entering the circulation shortly after their administration can alter the physiological properties of meningeal nociceptors and produce a transient exacerbation of headache. q
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Papers by Moshe Jakubowski