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1.
Front Neurosci ; 14: 22, 2020.
Article in English | MEDLINE | ID: mdl-32063832

ABSTRACT

Early life stress can exert detrimental or beneficial effects on neural development and postnatal behavior depending on the timing, duration, strength, and ability to control the stressors. In this study, we utilized a maternal and social deprivation (MSD) model to investigate the effects of early life stress on neural stem cells (NSCs) and neurogenesis in the adult brain. We found that MSD during the stress-hyporesponsive period (SHRP) (early-MSD), when corticosterone secretion is suppressed, increased the size of the NSC population, whereas the same stress beyond the SHRP abrogated these effects. Early-MSD enhanced neurogenesis not only in the dentate gyrus of the hippocampus, one of the classic neurogenic regions, but also in the amygdala. In addition, mice exposed to early-MSD exhibited a reduction in amygdala/hippocampus-dependent fear memory. These results suggest that animals exposed to early life stress during the SHRP have reinforced stress resilience to cope with perceived stressors to maintain a normal homeostatic state.

2.
Neurochem Res ; 43(1): 219-226, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29081002

ABSTRACT

Minocycline not only has antibacterial action but also produces a variety of pharmacological effects. It has drawn considerable attention as a therapeutic agent for symptoms caused by inflammation in many neurological disorders, leading to several clinical trials. Although some of these effects are mediated through its function of suppressing microglial activation, it is not clear whether minocycline acts on other cell types in the adult brain. In this study, we utilized a colony-forming neurosphere assay, in which neural stem cells (NSCs) clonally proliferate to form floating colonies, called neurospheres. We found that minocycline (at therapeutically relevant concentrations in cerebrospinal fluid) enhances the self-renewal capability of NSCs derived from the subependymal zone of adult mouse brain and facilitates their differentiation into oligodendrocytes. Importantly, these effects were independent of a suppression of microglial activation and were specifically observed with minocycline (among tetracycline derivatives). In addition, the size of the NSC population in the adult brain was increased when minocycline was infused into the lateral ventricle by an osmotic minipump in vivo. While precise molecular mechanisms of how minocycline alters the behavior of adult NSCs remain unknown, our data provide a basis for the clinical use of minocycline to treat neurodegenerative and demyelinating diseases.


Subject(s)
Cell Differentiation/drug effects , Cell Survival/drug effects , Minocycline/pharmacology , Neural Stem Cells/drug effects , Oligodendroglia/drug effects , Animals , Brain/drug effects , Cells, Cultured , Male , Mice , Neural Stem Cells/metabolism
3.
Neurochem Res ; 37(10): 2222-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22851351

ABSTRACT

Intradermal injection of an active compound of European honeybee toxin, melittin, into the forearm in humans produces temporary pain and evokes sustained increase of local skin temperature. This increase of skin temperature is suppressed by the pretreatment of a voltage gated sodium channel blocker, lidocaine, suggesting that neurogenic inflammation is involved in the skin temperature increase after the melittin treatment. In this study, we tested a hypothesis that the melittin-induced skin temperature increase is augmented by an N-methyl-D-aspartate (NMDA) glutamate receptor that is present on the peripheral terminals of cutaneous primary afferents. Skin temperature was examined after the local application of incremental doses of melittin by a computer-assisted-thermography in pentobarbital-anesthetized rats. Local subcutaneous glutamate was collected through a microdialysis probe and glutamate levels were measured by a high pressure liquid chromatography with electrochemical detection method. Intraplantar injection of melittin resulted in the increase of subcutaneous glutamate levels and the increase of local skin temperature, which was partially attenuated by co-injection of an NMDA receptor antagonist, MK-801. In addition, intraplantar injection of NMDA itself increased the local skin temperature. Our data suggest that melittin-induced increase of skin temperature is enhanced through the activation of peripheral NMDA receptors by locally released glutamate. We suggest that topical administration of NMDA receptor antagonists could be an effective treatment of neuro-inflammatory pain.


Subject(s)
Melitten/toxicity , Receptors, N-Methyl-D-Aspartate/physiology , Thermography , Animals , Chromatography, High Pressure Liquid , Male , Melitten/administration & dosage , Rats , Rats, Sprague-Dawley
4.
J Neurophysiol ; 93(6): 3594-604, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15659525

ABSTRACT

To elucidate the effect of chronic inflammation on spinal nociceptive neurons in the elderly, we compared nocifensive behavior, peripheral inflammatory responses, and spinal dorsal horn neuronal activities between the aged (29-34 mo) and adult (7-12 mo) male rats after injection of complete Freund's adjuvant (CFA) into the hind paw. Aged rats exhibited a significantly lower mechanical paw withdrawal threshold before inflammation. However, after CFA injection mechanical allodynia developed in both adult and aged rats after CFA injection. The changes of foot temperature and thickness after CFA injection were greater and lasted longer in aged than in adult rats. Sets of 124 wide dynamic range (WDR) neurons (aged: 59, adult: 65) and 26 nociceptive specific (NS) neurons (aged: 13, adult: 13) were recorded from the lumber spinal dorsal horn. NS neurons from the inflamed adult rats showed significantly higher responses to noxious mechanical stimulation than those in aged rats, whereas WDR neurons from inflamed adult and aged rats were similar. Background activity of WDR neurons from the adult rats increased after CFA, whereas WDR neurons of aged rats and NS neurons from either group were not. The afterdischarge followed by noxious mechanical stimulation was significantly greater for WDR neurons in both adult and aged rats, whereas no significant differences were observed in NS neurons. Two days after CFA injection, Fos expression increased similarly in aged and adult rats. Thus the aged rats showed enhanced peripheral inflammatory responses to CFA injection with only a slight change in dorsal horn neuronal activity. Together with our previous finding that nociceptive neurons in aged rats exhibit hyperexcitability, these results suggest that the dorsal horn nociceptive system becomes sensitized with advancing age and its excitability cannot be further increased by inflammation.


Subject(s)
Aging/physiology , Inflammation/physiopathology , Nociceptors/physiopathology , Pain/physiopathology , Posterior Horn Cells/physiopathology , Spinal Cord/cytology , Action Potentials/physiology , Action Potentials/radiation effects , Age Factors , Animals , Behavior, Animal , Body Temperature/physiology , Brain Mapping , Chronic Disease , Dose-Response Relationship, Radiation , Edema/pathology , Edema/physiopathology , Electric Stimulation/methods , Extremities/pathology , Extremities/physiopathology , Freund's Adjuvant , Functional Laterality , Inflammation/chemically induced , Inflammation/pathology , Male , Pain/pathology , Pain Measurement/methods , Pain Threshold , Physical Stimulation/adverse effects , Rats , Rats, Inbred F344 , Time Factors
5.
Eur J Pain ; 6(6): 447-53, 2002.
Article in English | MEDLINE | ID: mdl-12413433

ABSTRACT

Melittin is the main toxin of honeybee venom. Previously, we have reported that intradermal injection of melittin into the volar aspect of forearm in humans produces a temporary pain and a subsequent sustained increase in the skin temperature due to axon reflex. To clarify the interaction between nociceptive inputs and vascular changes, we studied the influence of noxious stimulation by intradermal melittin on the vasomotor control of the distal extremities in human volunteers. Temperature changes of the bilateral palmar surface were recorded by means of a computer-assisted infrared thermography. Unexpectedly, we found a biphasic response of skin temperature. The skin temperature of both fingers and hands decreased immediately after the melittin injection and then increased well above the control level, prior to the injection. There was a considerable individual variation in the baseline skin temperature, prior to melittin. The skin temperature in a finger/hand with lower preinjection value increased more markedly in the second phase. Consequently, the individual variation in the peak temperature of the second phase was less pronounced. The initial decrease was interpreted as sympathetic vasoconstrictor reflex induced by noxious stimulation and the later increase as release of sympathetic vasomotor tone.


Subject(s)
Blood Vessels/drug effects , Melitten/pharmacology , Reflex/drug effects , Skin/drug effects , Sympathetic Fibers, Postganglionic/drug effects , Vasoconstriction/drug effects , Vasomotor System/drug effects , Adult , Blood Vessels/innervation , Female , Functional Laterality/drug effects , Functional Laterality/physiology , Humans , Male , Nerve Fibers, Unmyelinated/drug effects , Nerve Fibers, Unmyelinated/physiology , Nociceptors/drug effects , Nociceptors/physiology , Pain/chemically induced , Pain/physiopathology , Pain Measurement/drug effects , Reflex/physiology , Skin/innervation , Skin Temperature/drug effects , Skin Temperature/physiology , Sympathetic Fibers, Postganglionic/physiology , Vasoconstriction/physiology , Vasodilation/drug effects , Vasodilation/physiology , Vasomotor System/physiology
6.
Pain ; 76(3): 327-336, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9718251

ABSTRACT

Effects of intravenous administration of picrotoxin (PTX), a GABA(A) receptor antagonist, upon activities of wide dynamic range (WDR) neurons in the lumbar spinal cord were studied in urethane-chloralose anesthetized cats. Intravenous PTX augmented tactile evoked responses of WDR neurons, but reduced nociceptive responses dose-dependently. Spinal transection reversed the suppression of nociceptive responses. In the spinal cat, intravenous PTX enhanced the tactile evoked response. Intravenous PTX enhanced the spontaneous firing of nucleus raphe dorsalis (NRD) and/or ventral periaqueductal gray (PAG) neurons projecting to nucleus raphe magnus. Lidocaine injected into NRD/PAG reversed the antinociceptive action of intravenous PTX. PTX injected into NRD/PAG reduced heat-evoked responses of WDR units. These data suggest that antinociceptive effects of intravenous PTX is primarily due to disinhibitory activation of the descending antinociceptive system originating from NRD and PAG, and that PTX reinforces touch-evoked responses in the spinal cord.


Subject(s)
Analgesics/pharmacology , GABA Antagonists/pharmacology , GABA-A Receptor Antagonists , Pain/physiopathology , Picrotoxin/pharmacology , Touch/physiology , Anesthetics, Local/pharmacology , Animals , Brain Mapping , Cats , Decerebrate State , Electrophysiology , GABA Antagonists/administration & dosage , Hot Temperature , Lidocaine/pharmacology , Microinjections , Neurons/drug effects , Periaqueductal Gray/drug effects , Periaqueductal Gray/physiopathology , Physical Stimulation , Raphe Nuclei/drug effects , Raphe Nuclei/physiopathology , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/physiopathology , Touch/drug effects
7.
J Anesth ; 11(3): 184-192, 1997 Sep.
Article in English | MEDLINE | ID: mdl-28921109

ABSTRACT

PURPOSE: To clarify whether ketamine suppresses both A-fiber-and C-fiber-mediated pain and to compare the effects of ketamine with those of MK-801. METHODS: Experiments were performed on urethane/chloralose-anesthetized cats. Glass capillary microelectrodes were used to record extracellular single unit activities from wide dynamic range (WDR) neurons in the spinal dorsal horn. Responses evoked by electrical stimulation of the superficial peroneal (SP), posterior tibial (PT), or both nerves were analyzed. The responses to successive electrical stimuli were displayed on a personal computer using a raster-dot processing program. RESULTS: A subanesthetic dose of intravenous ketamine suppressed both A- and C-fiber responses of WDR neurons in a dose-dependent manner without affecting A-fiber response of low-threshold mechanoreceptive (LTM) neurons. The C-fiber response was more markedly suppressed than the A-fiber response. Intravenous administration of MK-801, a specificN-methyl-D-aspartate (NMDA) antagonist, selectively suppressed the C-fiber response of WDR neurons. CONCLUSION: Intravenous ketamine may suppress both A-and C-fiber-mediated pain at a subanesthetic dose. This finding could be a scientific basis for the usefulness of ketamine during clinical procedures such as dressing changes or débridement of the burned patient.

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