Biomedical subjects

Peggy Mason

Publications and source records attributed to Peggy Mason.

12 recordsLinked to original sources

PubMed2006

Raphe magnus neurons help protect reactions to visceral pain from interruption by cutaneous pain.

Suppression of reactions to one noxious stimulus by a spatially distant noxious stimulus is termed heterotopic antinociception. In lightly anesthetized rats, a noxious visceral stimulus, colorectal distension (CRD), suppressed motor withdrawals but not blood pressure or heart rate changes evoked by noxious hindpaw heat. Microinjection of muscimol, a GABA(A) receptor agonist, into raphe magnus (RM) reduced CRD-evoked suppression of withdrawals, evidence that RM neurons contribute to this heterotopic antinociception. To understand how brain stem neurons contribute to heterotopic antinociception, RM neurons were recorded during CRD-elicited suppression of hindpaw withdrawals. Although subsets of RM neurons that were excited (on cells) or inhibited (off cells) by noxious cutaneous stimulation were either excited or inhibited by CRD, on cells were inhibited and off cells excited by an intracerebroventricularly administered opioid, evidence that the nociception-facilitating and -inhibiting functions of on and off cells, respectively, are predicted by the cellular response to noxious cutaneous stimulation alone and not by the response to CRD. When recorded during CRD-elicited antinociception, RM cell discharge resembled the pattern observed in response to CRD stimulation alone. However, when hindpaw withdrawal suppression was incomplete, RM cell discharge resembled the pattern observed in response to heat alone. We propose that on cells excited by CRD facilitate responses to CRD itself, which in turn augments excitation of off cells that then act to suppress cutaneous nociception. RM cells may thereby contribute to the dominance of quiet recuperative reactions evoked by potentially life-threatening visceral stimuli over transient somatomotor activity elicited by less-injurious noxious cutaneous stimuli.

Analgesics, Opioid↗

PubMed2006

Medullary raphe neurons facilitate brown adipose tissue activation.

Recent evidence suggests that neurons in the medullary raphe are critical to the activation of brown adipose tissue (BAT), the major source of nonshivering heat production in the rat. Yet it is unclear which medullary raphe cells participate in cold defense and how participating cells contribute to BAT activation. Therefore, we recorded extracellularly from raphe cells during three thermoregulatory challenges that evoked an increase in BAT temperature in anesthetized rats: central cold, ambient cold, or intracerebroventricular prostaglandin E2 (PGE2) injection. Physiologically identified serotonergic (p5HT) cell discharge increased in response to cold or PGE2 administration and was positively correlated with BAT temperature. However, none of the 147 physiologically identified non-serotonergic (non-p5HT) cells recorded responded to thermoregulatory challenges that evoked an increase in BAT temperature. To test for modulation of BAT activation by non-p5HT cells that are either excited (ON cells) or inhibited (OFF cells) by noxious cutaneous stimulation, noxious stimuli were applied during evoked BAT temperature increases. Noxious stimulation suppressed BAT activation, suggesting that cells inhibited by noxious stimulation facilitate spinal circuits controlling BAT. To test whether medullary OFF cells modulate BAT activity, the mu-opiate receptor agonist (d-Ala2, N-Me-Phe4, Gly-ol5)-enkephalin (DAMGO) was microinjected into the raphe magnus, a manipulation that selectively activates OFF cells. DAMGO microinjection blocked noxious stimulation-evoked suppression of PGE2-induced BAT temperature increases. Thus, both p5HT and non-p5HT OFF cells in the medullary raphe facilitate BAT activation in response to cold challenge or pyrogen.

Adipose Tissue, Brown↗

PubMed2005

Ventromedial medulla: pain modulation and beyond.

The midbrain periaqueductal gray (PAG) and ventromedial medulla (VMM) are generally viewed as the core of an endogenous descending modulatory system. However, available data demonstrate that PAG and VMM do not specifically target nociceptive transmission and that activation of either structure affects numerous homeostatic physiological processes. Pseudorabies virus (PRV) is a useful tracer that is retrogradely and transynaptically transported. PRV injections into homeostatic effector organs invariably label VMM neurons, both serotonergic and nonserotonergic. Studies in anesthetized rats have implicated two types of nonserotonergic VMM neurons in nociceptive modulation: ON cells are thought to facilitate nociception and OFF cells to inhibit nociception. Yet, in the unanesthetized animal, the discharge of VMM neurons changes in response to innocuous stimuli and during situations unrelated to nociception. In particular, VMM cells appear to modulate the timing of micturition, with ON cells promoting the initiation of voiding and OFF cells promoting urine storage. VMM cells also modulate sensory transmission. During both micturition and sleep, OFF cells discharge and sensory responsiveness is depressed. In sum, the VMM is hypothesized to modulate spinal sensory, autonomic, and motor circuits in order to maintain homeostasis.

Animals↗

PubMed2005

Sensory suppression during feeding.

Feeding is essential for survival, whereas withdrawal and escape reactions are fundamentally protective. These critical behaviors can compete for an animal's resources when an acutely painful stimulus affects the animal during feeding. One solution to the feeding-withdrawal conflict is to optimize feeding by suppressing pain. We examined whether rats continue to feed when challenged with a painful stimulus. During feeding, motor withdrawal responses to noxious paw heat either did not occur or were greatly delayed. To investigate the neural basis of sensory suppression accompanying feeding, we recorded from brainstem pain-modulatory neurons involved in the descending control of pain transmission. During feeding, pain-facilitatory ON cells were inhibited and pain-inhibitory OFF cells were excited. When a nonpainful somatosensory stimulus preactivated ON cells and preinhibited OFF cells, rats interrupted eating to react to painful stimuli. Inactivation of the brainstem region containing ON and OFF cells also blocked pain suppression during eating, demonstrating that brainstem pain-modulatory neurons suppress motor reactions to external stimulation during homeostatic behaviors.

Animals↗

PubMed2005

Roles for pain modulatory cells during micturition and continence.

We studied how the nervous system selects between noxious stimulus-evoked withdrawals and micturition, movements that are necessary for survival but use overlapping muscles and therefore cannot occur simultaneously. In lightly anesthetized rats, micturition was favored, because noxious stimulation never interrupted micturition, whereas withdrawals were suppressed during voiding. Neurons in the ventromedial medulla (VMM) are a major source of descending antinociceptive signals. To test whether VMM neurons support withdrawal suppression during micturition, the discharge of VMM neurons was recorded during continence and micturition. VMM cells that were inhibited (M-inh) or excited (M-exc) during micturition were observed. M-inh cells were excited by noxious cutaneous stimulation and thus are likely nociception facilitating, whereas M-exc cells were inhibited by noxious heat and are likely nociception inhibiting. The excitation of nociception-inhibiting M-exc and inhibition of nociception-facilitating M-inh cells predicts suppression of withdrawals during micturition. M-exc cells were typically silent before micturition, whereas most M-inh cells fired before micturition, suggesting that these cells may also play a preparatory role for micturition. To test this idea, we examined manipulations that either advanced or delayed the onset of micturition. Hypothalamic stimulation and noxious paw heat advanced micturition while exciting M-inh cells and inhibiting M-exc cells. In contrast, colorectal distension, a stimulus that delays micturition, inhibited M-inh cells and excited M-exc cells. These results suggest a model in which, during continence, VMM M-inh cells facilitate and M-exc cells inhibit bladder afferents, advancing micturition onset when M-inh cells are activated and delaying onset when M-exc cells are activated.

Animals↗

PubMed2005

Deconstructing endogenous pain modulations.

A pathway from the midbrain periaqueductal gray (PAG) through the ventromedial medulla (VMM) to the dorsal horn constitutes a putative endogenous nociceptive modulatory system. Yet activation of neurons in both PAG and VMM changes the responses of dorsal horn cells to non-noxious stimuli and elicits motor and autonomic reactions that are not directly related to nociception. Activation of mu-opioid receptors in VMM and PAG also modifies processes in addition to nociceptive transmission. The descending projections of VMM neurons are not specific to nociception as VMM projects to the spinal superficial dorsal horn where thermoreceptors as well as nociceptors terminate. In addition, experiments with pseudorabies virus demonstrate multi-synaptic pathways from VMM to sympathetic and parasympathetic target organs. VMM neurons respond to both noxious and unexpected innocuous stimuli of multiple modalities, and change their discharge during behaviors unrelated to pain such as micturition/continence and sleep/wake. In conclusion, all available evidence argues against the idea that PAG and VMM target nociception alone. Instead these brain stem sites may effect homeostatic adjustments made necessary by salient situations including but not limited to injury.

Animals↗

PubMed2004

Movement-related discharge of ventromedial medullary neurons.

Studies in anesthetized animals implicate nonserotonergic cells in the ventromedial medulla (VMM) in opioid modulation of nociceptive transmission but do not reveal the conditions that engage VMM cells in unanesthetized rats. The few studies of VMM cells in unanesthetized rats show that VMM cells change their discharge across the sleep-wake cycle and during active movements. Since active movements are more likely to occur during waking than sleep, state-related discharge may in fact represent movement-related discharge. In this study, we recorded the discharge of VMM neurons in unanesthetized, drug-free, freely moving rats and examined whether neuronal activity was related to wake/sleep state, to motor activity, or to both factors. Most cells (45/67) were more active during waking states than sleeping states, 1 cell was more active during sleep states, and the remaining 21 cells did not fire preferentially across the sleep-wake cycle. Most wake-active cells (36/45) showed discharge bursts during movement bursts, and 9/11 wake-active cells were excited by noxious heat and innocuous air puff stimulation. In contrast, few state-independent cells (9/21) showed movement-related bursts in discharge. These results suggest that VMM neurons modulate spinal processes during phasic motor activity.

Action Potentials↗

PubMed2004

Role for raphe magnus neuronal responses in the behavioral reactions to colorectal distension.

The brain stem is necessary for the expression of behavioral reactions to noxious visceral inputs. Neurons in raphe magnus (RM) and the adjacent nucleus reticularis magnocellularis (NRMC) respond to visceral stimuli and can facilitate the behavioral reaction to visceral stimulation. To determine which RM and NRMC cells could play a role in generating the reaction to colorectal distension (CRD), the responses of RM and NRMC cells to multiple intensities of CRD were compared with simultaneously evoked cardiovascular and visceromotor reactions in halothane-anesthetized rats. Most neurons (89%) responded to CRD with one of three basic response patterns. For cells with a graded response pattern, the response magnitude increased with increasing stimulation intensity. For flat responding cells, the response magnitude was not different across suprathreshold stimulation intensities. Finally, neurons with a switch response pattern responded to low- and high-intensity CRD in opposing directions. Cells were either inhibited or excited by CRD in each of these categories. Responses of cells with both graded and switch response patterns were significantly correlated with CRD-evoked tachycardia, pressor reaction, and hunching. The activity of graded-responding cells have the greatest predictive value for CRD-evoked reactions. Flat-responding cells have nonlinear responses that may augment reactions to stimuli above the noxious threshold. Cells with switch type response patterns may contribute to differential reactions evoked by CRD stimuli within the noxious range. In sum, RM and NRMC neurons respond to CRD with a variety of patterns, each of which may contribute to the sculpting of CRD reactions in different ways.

Animals↗

PubMed2004

Modulation of sympathetic and somatomotor function by the ventromedial medulla.

The ventromedial medulla is implicated in a variety of functions including nociceptive and cardiovascular modulation and the control of thermoregulation. To determine whether single microinjections into the ventromedial medulla elicit changes in one or multiple functional systems, the GABA(A) receptor antagonist bicuculline was microinjected (70 nl, 5-50 ng) into the ventromedial medulla of lightly anesthetized rats, and cardiovascular, respiratory, and nociceptive measures were recorded. Bicuculline microinjection into either the midline raphe or the laterally adjacent reticular nucleus simultaneously increased interscapular brown adipose tissue temperature, heart rate, blood pressure, expired [CO(2)], and respiration rate and elicited shivering. Bicuculline microinjection also decreased the noxious stimulus-evoked changes in heart rate and blood pressure, decreased the frequency of heat-evoked sighs, and suppressed the cortical desynchronization evoked by noxious stimulation. Although bicuculline suppressed the motor withdrawal evoked by noxious tail heat, it enhanced the motor withdrawal evoked by noxious paw heat, evidence for specifically patterned nociceptive modulation. Saline microinjections into midline or lateral sites had no effect on any measured variable. All bicuculline microinjections, midline or lateral, evoked the same set of physiological effects, consistent with the lack of a topographical organization within the ventromedial medulla. Furthermore, as predicted by the isodendritic morphology of cells in the ventromedial medulla, midline bicuculline microinjection increased the number of c-fos immunoreactive cells in both midline raphe and lateral reticular nuclei. In summary, 70-nl microinjections into ventromedial medulla activate cells in multiple nuclei and elicit increases in sympathetic and somatomotor tone and a novel pattern of nociceptive modulation.

Adrenergic Fibers↗

PubMed2003

Discharge of raphe magnus ON and OFF cells is predictive of the motor facilitation evoked by repeated laser stimulation.

Medullary raphe magnus (RM) on and off cells are thought to modulate spinal nociception by gating withdrawals evoked by noxious stimulation. To test whether withdrawal initiation is the target of RM modulation, we examined the relationship between on and off cell discharge and motor withdrawal evoked by noxious laser heat in halothane-anesthetized rats. The cellular responses of both cell types began during the 50 msec after onset of the tail flick, peaked within 200 msec, and outlasted the duration of the motor reaction. Thus, it is unlikely that the target of on and off cell modulation is withdrawal initiation; instead, on and off cells may modulate reactions to repeated noxious stimulation. We therefore tested whether laser heat-evoked changes in RM cell discharge were predictive of the modulatory effects of one noxious stimulus on the reaction to a subsequent noxious stimulus. Two pulses of laser heat were presented at interpulse intervals of 0.8, 2.0, or 10.0 sec. The motor withdrawal evoked by the second pulse was significantly enhanced relative to that evoked by the first pulse. The observed motor enhancement depended on supraspinal input because it was not present in spinalized rats. Comparison of the relative changes in motor and cellular activity preceding double laser heat stimulation revealed parallel changes between motor facilitation, decreases in off cell discharge, and increases in on cell discharge. This finding suggests a preparatory role for RM on and off cells in enhancing reactions to a noxious stimulus that closely follows another noxious stimulus.

Action Potentials↗

PubMed2003

Brainstem modulation of pain during sleep and waking.

Moderately painful stimuli applied during sleep evoke motor and neural responses indicative of arousal, but seldom cause awakening. Different reactions occur in response to acute pain stimulation across behavioral states; pain reactions are modulated by the activity of serotonergic and non-serotonergic cells in the raphe magnus (RM). Serotonergic RM cells have state-dependent discharge and may inhibit simple motor withdrawal responses during waking. ON and OFF cells are non-serotonergic RM neurons thought to facilitate and inhibit pain, respectively. These cells display reciprocal spontaneous discharge patterns across the sleep-wake cycle, with ON cells most active during waking and OFF cells most active during sleep. We propose that they also play an important role in modulating the alertness evoked by any brief external stimulus, either noxious or innocuous. ON cells may facilitate alertness during waking and OFF cells suppress arousals during sleep. In the presence of chronic pain, both ON and OFF cell discharge appear to increase. The increase in ON cell discharge may contribute to enhancing pain sensitivity and alertness. Future research is needed to understand why sleep is so adversely affected in chronic pain patients, whereas sleep is minimally disrupted, even by acutely painful stimuli, in humans and animals without chronic pain.

Animals↗

PubMed2002

Raphe magnus neurons respond to noxious colorectal distension.

Physiological studies of neurons in raphe magnus (RM) and the adjacent nucleus reticularis magnocellularis (NRMC) have demonstrated that the response to noxious cutaneous stimulation predicts the response to opioid administration and therefore a cell's functional role in nociceptive modulation. Although visceral stimulation, like opioids, elicits antinociception, little is known about how RM and NRMC cells respond to visceral stimulation. Therefore RM and NRMC cells were tested for their responses to both colorectal distension (CRD) and noxious cutaneous heat in halothane-anesthetized rats. Less than a third of serotonergic cells responded to CRD with small increases or decreases in discharge rate. In contrast, almost two-thirds of nonserotonergic cells responded to CRD stimulation with either excitatory (35%) or inhibitory (30%) responses to CRD. The response to heat did not predict the response to CRD with nearly equal proportions of heat-excited, -inhibited, and -unaffected cells being excited, inhibited, or unaffected by CRD. The dissociation between the responses to cutaneous heat and CRD demonstrates that cell classes based on the response to noxious heat are not homogeneous and may play multiple functional roles.

Animals↗