min zhuo - Academia.edu (original) (raw)

Papers by min zhuo

Research paper thumbnail of Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats

Brain Research, 1998

It is documented that spinal nociceptive transmission receives descending facilitatory and inhibi... more It is documented that spinal nociceptive transmission receives descending facilitatory and inhibitory modulation from supraspinal structures. The rostral ventral medulla (RVM), including the nucleus raphe magnus (NRM), nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGCalpha), is the major bulbar relay of descending modulatory influences. Pharmacological studies show that facilitation of a spinal nociceptive tail-flick (TF) reflex induced by stimulation in the NGC and NGCalpha is mediated by spinal serotonergic receptors. The present series of experiments provide evidence that activation of spinal serotonergic systems are critical for both induction and maintenance of secondary hyperalgesia induced by subcutaneous injection of formalin into one hindpaw. Subcutaneous injection of formalin produced facilitation of tail withdrawal (mechanical) and the TF reflex (thermal). Facilitatory effects persisted for at least 30 min. Peripheral blockade of the activity by local injection of a hydrophilic lidocaine derivative (QX-314, 5%) into the injected hindpaw abolished both mechanical and thermal facilitation, indicating that peripheral input is important to maintain long-lasting facilitation. Intrathecal application of a serotonergic receptor antagonist methysergide at a dose (64 nmol) which completely blocked descending facilitation produced by electrical- or chemical-stimulation in the NGC and NGCalpha also significantly attenuated or completely abolished facilitation of tail withdrawal and the TF reflex induced by formalin. Methysergide was effective whether the injection was performed before or after the formalin injection. These results suggest that activation of descending facilitatory serotonergic influences by a prolonged noxious stimulation could contribute to secondary hyperalgesia observed at the tail.

Research paper thumbnail of Genetic Elimination of Behavioral Sensitization in Mice Lacking Calmodulin-Stimulated Adenylyl Cyclases

Neuron, 2002

Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases... more Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.

Research paper thumbnail of Pavlovian fear memory induced by activation in the anterior cingulate cortex

Molecular Pain, 2005

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is... more Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA A receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception.

Research paper thumbnail of Sex differences in late behavioral response to subcutaneous formalin injection in mice

Brain Research, 1999

We investigated sex-or gender-dependent differences in nociception using the formalin test in mic... more We investigated sex-or gender-dependent differences in nociception using the formalin test in mice. In addition to typical biphasic Ž . responses, a new, late phase Phase 3 was observed. A local anesthetic QX-314 injected at the end of Phase 2 blocked Phase 3. Phase 3 in female mice was significantly greater than that in male mice regardless the stage of the estrus cycle. q 1999 Elsevier Science B.V. All rights reserved.

Research paper thumbnail of Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat

Journal of Physiology-london, 2001

Research paper thumbnail of Calcium–calmodulin-dependent protein kinase IV is required for fear memory

Nature Neuroscience, 2002

Research paper thumbnail of AMPA receptor–PDZ interactions in facilitation of spinal sensory synapses

Nature Neuroscience, 1999

Here we demonstrate that protein interactions involving the GluR2/3 C terminus are important for ... more Here we demonstrate that protein interactions involving the GluR2/3 C terminus are important for serotonin-induced activation of silent synapses in the spinal cord. Furthermore, PKC is a necessary and sufficient trigger for this activation. These results implicate AMPA receptor-PDZ interactions in mechanisms underlying sensory synaptic potentiation and provide insights into the pathogenesis of chronic pain.

Research paper thumbnail of Loss of Synaptic Depression in Mammalian Anterior Cingulate Cortex after Amputation

Two forms of activity-dependent long-term depression (LTD) in the CNS, as defined by their sensit... more Two forms of activity-dependent long-term depression (LTD) in the CNS, as defined by their sensitivity to the blockade of NMDA receptors, are thought to be important in learning, memory, and development. Here, we report that NMDA receptorindependent LTD is the major form of long-term plasticity in the anterior cingulate cortex (ACC). Both L-type voltage-gated calcium channels and metabotropic glutamate receptors are required for inducing LTD. Amputation of a third hindpaw digit in an adult rat induced rapid expression of immediate early genes in the ACC bilaterally and caused a loss of LTD that persisted for at least 2 weeks. Our results suggest that synaptic LTD in the ACC may contribute to enhanced neuronal responses to subsequent somatosensory stimuli after amputation.

Research paper thumbnail of ATP P2X receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats

Slices were fixed in cold 10 mM phosphate-buffered saline Intrathecal drug administration (PBS; p... more Slices were fixed in cold 10 mM phosphate-buffered saline Intrathecal drug administration (PBS; pH 7.2) containing 4% paraformaldeyhde (1-7 days at 4ЊC) and were then rinsed several times for 10 min each in PBS. To

Research paper thumbnail of Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex

European Journal of Pain, 2000

It is well documented that the descending endogenous analgesia system, including the periaqueduct... more It is well documented that the descending endogenous analgesia system, including the periaqueductal gray (PAG) and the rostral ventral medulla (RVM), play an important role in modulation of nociceptive transmission and morphine-and cannabinoid-produced analgesia. Neurons in the PAG receive inputs from different nuclei of higher structures, including the anterior cingulate cortex (ACC). However, it is unclear if stimulation of neurons in the ACC modulates spinal nociceptive transmission. The present study has examined the effects of electrical stimulation and chemical activation of metabotropic glutamate receptors (mGluRs) in the ACC on a spinal nociceptive tail-flick (TF) reflex induced by noxious heating. Activation of the ACC at high intensities (up to 500 µA) of electrical stimulation did not produce any antinociceptive effect. Instead, at most sites within the ACC (n = 36 of 41 sites), electrical stimulation produced significant facilitation of the TF reflex (i.e. decreases in TF latency). Chemical activation of mGluRs within the ACC also produced a facilitatory effect. Descending facilitation from the ACC apparently relays at the RVM. Electrical stimulation in the RVM produces a biphasic modulatory effect, showing facilitation at low intensities and inhibition at higher intensities. The present study provides evidence that activation of mGluRs within the ACC can facilitate spinal nociception.

Research paper thumbnail of Comparison of behavioral responses to noxious cold and heat in mice

Brain Research, 1999

We investigated behavioral responses to noxious cold and heat stimuli in mice. Similar to the hot... more We investigated behavioral responses to noxious cold and heat stimuli in mice. Similar to the hot-plate test, mice showed licking or jumping responses on a cold-plate (0 degrees C). The sensitivity to noxious heat (55 degrees C) was not correlated to the sensitivity to noxious cold, indicating that nociceptive processing of cold and heat are different. Behavioral responses to noxious cold are inhibited by systemic morphine or intrathecal administration of morphine. Lesion of the medial frontal cortex, including the anterior cingulate cortex, or selective activation of two types of opioid receptors in the anterior cingulate cortex produces dose-dependent antinociceptive effects on behavioral responses to noxious cold stimuli. These results suggest that activation of opioid receptors in the anterior cingulate cortex can produce powerful antinociception.

Research paper thumbnail of Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats

Brain Research, 1998

It is documented that spinal nociceptive transmission receives descending facilitatory and inhibi... more It is documented that spinal nociceptive transmission receives descending facilitatory and inhibitory modulation from supraspinal structures. The rostral ventral medulla (RVM), including the nucleus raphe magnus (NRM), nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGCalpha), is the major bulbar relay of descending modulatory influences. Pharmacological studies show that facilitation of a spinal nociceptive tail-flick (TF) reflex induced by stimulation in the NGC and NGCalpha is mediated by spinal serotonergic receptors. The present series of experiments provide evidence that activation of spinal serotonergic systems are critical for both induction and maintenance of secondary hyperalgesia induced by subcutaneous injection of formalin into one hindpaw. Subcutaneous injection of formalin produced facilitation of tail withdrawal (mechanical) and the TF reflex (thermal). Facilitatory effects persisted for at least 30 min. Peripheral blockade of the activity by local injection of a hydrophilic lidocaine derivative (QX-314, 5%) into the injected hindpaw abolished both mechanical and thermal facilitation, indicating that peripheral input is important to maintain long-lasting facilitation. Intrathecal application of a serotonergic receptor antagonist methysergide at a dose (64 nmol) which completely blocked descending facilitation produced by electrical- or chemical-stimulation in the NGC and NGCalpha also significantly attenuated or completely abolished facilitation of tail withdrawal and the TF reflex induced by formalin. Methysergide was effective whether the injection was performed before or after the formalin injection. These results suggest that activation of descending facilitatory serotonergic influences by a prolonged noxious stimulation could contribute to secondary hyperalgesia observed at the tail.

Research paper thumbnail of Genetic Elimination of Behavioral Sensitization in Mice Lacking Calmodulin-Stimulated Adenylyl Cyclases

Neuron, 2002

Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases... more Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.

Research paper thumbnail of Pavlovian fear memory induced by activation in the anterior cingulate cortex

Molecular Pain, 2005

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is... more Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA A receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception.

Research paper thumbnail of Sex differences in late behavioral response to subcutaneous formalin injection in mice

Brain Research, 1999

We investigated sex-or gender-dependent differences in nociception using the formalin test in mic... more We investigated sex-or gender-dependent differences in nociception using the formalin test in mice. In addition to typical biphasic Ž . responses, a new, late phase Phase 3 was observed. A local anesthetic QX-314 injected at the end of Phase 2 blocked Phase 3. Phase 3 in female mice was significantly greater than that in male mice regardless the stage of the estrus cycle. q 1999 Elsevier Science B.V. All rights reserved.

Research paper thumbnail of Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat

Journal of Physiology-london, 2001

Research paper thumbnail of Calcium–calmodulin-dependent protein kinase IV is required for fear memory

Nature Neuroscience, 2002

Research paper thumbnail of AMPA receptor–PDZ interactions in facilitation of spinal sensory synapses

Nature Neuroscience, 1999

Here we demonstrate that protein interactions involving the GluR2/3 C terminus are important for ... more Here we demonstrate that protein interactions involving the GluR2/3 C terminus are important for serotonin-induced activation of silent synapses in the spinal cord. Furthermore, PKC is a necessary and sufficient trigger for this activation. These results implicate AMPA receptor-PDZ interactions in mechanisms underlying sensory synaptic potentiation and provide insights into the pathogenesis of chronic pain.

Research paper thumbnail of Loss of Synaptic Depression in Mammalian Anterior Cingulate Cortex after Amputation

Two forms of activity-dependent long-term depression (LTD) in the CNS, as defined by their sensit... more Two forms of activity-dependent long-term depression (LTD) in the CNS, as defined by their sensitivity to the blockade of NMDA receptors, are thought to be important in learning, memory, and development. Here, we report that NMDA receptorindependent LTD is the major form of long-term plasticity in the anterior cingulate cortex (ACC). Both L-type voltage-gated calcium channels and metabotropic glutamate receptors are required for inducing LTD. Amputation of a third hindpaw digit in an adult rat induced rapid expression of immediate early genes in the ACC bilaterally and caused a loss of LTD that persisted for at least 2 weeks. Our results suggest that synaptic LTD in the ACC may contribute to enhanced neuronal responses to subsequent somatosensory stimuli after amputation.

Research paper thumbnail of ATP P2X receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats

Slices were fixed in cold 10 mM phosphate-buffered saline Intrathecal drug administration (PBS; p... more Slices were fixed in cold 10 mM phosphate-buffered saline Intrathecal drug administration (PBS; pH 7.2) containing 4% paraformaldeyhde (1-7 days at 4ЊC) and were then rinsed several times for 10 min each in PBS. To

Research paper thumbnail of Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex

European Journal of Pain, 2000

It is well documented that the descending endogenous analgesia system, including the periaqueduct... more It is well documented that the descending endogenous analgesia system, including the periaqueductal gray (PAG) and the rostral ventral medulla (RVM), play an important role in modulation of nociceptive transmission and morphine-and cannabinoid-produced analgesia. Neurons in the PAG receive inputs from different nuclei of higher structures, including the anterior cingulate cortex (ACC). However, it is unclear if stimulation of neurons in the ACC modulates spinal nociceptive transmission. The present study has examined the effects of electrical stimulation and chemical activation of metabotropic glutamate receptors (mGluRs) in the ACC on a spinal nociceptive tail-flick (TF) reflex induced by noxious heating. Activation of the ACC at high intensities (up to 500 µA) of electrical stimulation did not produce any antinociceptive effect. Instead, at most sites within the ACC (n = 36 of 41 sites), electrical stimulation produced significant facilitation of the TF reflex (i.e. decreases in TF latency). Chemical activation of mGluRs within the ACC also produced a facilitatory effect. Descending facilitation from the ACC apparently relays at the RVM. Electrical stimulation in the RVM produces a biphasic modulatory effect, showing facilitation at low intensities and inhibition at higher intensities. The present study provides evidence that activation of mGluRs within the ACC can facilitate spinal nociception.

Research paper thumbnail of Comparison of behavioral responses to noxious cold and heat in mice

Brain Research, 1999

We investigated behavioral responses to noxious cold and heat stimuli in mice. Similar to the hot... more We investigated behavioral responses to noxious cold and heat stimuli in mice. Similar to the hot-plate test, mice showed licking or jumping responses on a cold-plate (0 degrees C). The sensitivity to noxious heat (55 degrees C) was not correlated to the sensitivity to noxious cold, indicating that nociceptive processing of cold and heat are different. Behavioral responses to noxious cold are inhibited by systemic morphine or intrathecal administration of morphine. Lesion of the medial frontal cortex, including the anterior cingulate cortex, or selective activation of two types of opioid receptors in the anterior cingulate cortex produces dose-dependent antinociceptive effects on behavioral responses to noxious cold stimuli. These results suggest that activation of opioid receptors in the anterior cingulate cortex can produce powerful antinociception.