Sheralee Tershner | Western New England University (original) (raw)
Papers by Sheralee Tershner
Pharmacology, Biochemistry and Behavior, Aug 1, 1997
A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, an... more A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.
Neuroscience, Oct 1, 2000
The rostral ventromedial medulla contains three physiologically defined classes of pain-modulatin... more The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the placeconditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the a 1-adrenoceptor agonist methoxamine (50.0 mg in 0.5 ml; to activate ON cells, primarily), combined with local microinjection of the k-opioid receptor agonist U69,593 (0.178 mg in 0.5 ml; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69,593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.
Nature, Sep 1, 1997
The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primaril... more The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.
American Journal of Physiology-renal Physiology, Aug 1, 1991
Evidence that the renal sympathetic nerves have direct effects on renal tubular function suggests... more Evidence that the renal sympathetic nerves have direct effects on renal tubular function suggests that neurogenic mechanisms may play an important role in the daily regulation of sodium balance. We evaluated the influence of the renal nerves on the rate of elevating urinary sodium excretion (UNaV) after a step increase in fixed sodium intake. Conscious rats with innervated (INN) or denervated (DNX) kidneys were placed on low-sodium intake (LNa = 0.3 meq/day) or a normal sodium intake (NNa = 1.0 meq/day) by intravenous infusion. Hourly changes in UNaV were determined 24 h before and 72 h after increasing sodium intake to either NNa or high-sodium intake (HNa = 5.0 meq/day). Switching from LNa to NNa, INN rats increased UNaV within 24 h; however, DNX rats did not begin to increase UNaV until hour 60. Cumulative sodium balance over 72 h was more positive in DNX rats (INN = 1.29 +/- 0.29 meq; DNX = 2.06 +/- 0.21 meq, P less than 0.05). During the LNa-to-HNa switch, both INN and DNX rats increased UNaV equally for 12 h; however, at this time INN rats continued to increase UNaV, whereas DNX rats did not. DNX rats had a net accumulation of 2.54 meq more sodium than INN rats over 72 h. Significant inhibition of plasma renin activity within the first 24 h occurred only in rats receiving the LNa-to-HNa switch in sodium intake, and this response was not different between rats with innervated and denervated kidneys. These data suggest that the renal nerves provide a rapid sodium excretory response to step increases in sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Neuroreport, Oct 1, 1999
THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid re... more THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the ìopioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[ø] or the DOR 2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[ø] (1.0 ìg) and NTB (5.0 ng) signi®cantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results con®rm and extend previous studies suggesting that PAG ì-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.
Psychobiology, Mar 1, 1996
CeA. One study demonstrated that direct application of ahelical CRF 9 _ 41 into the CeA dose-depe... more CeA. One study demonstrated that direct application of ahelical CRF 9 _ 41 into the CeA dose-dependently reversed the heightened emotionality of socially defeated rats (Heinrichs et ai., 1992). In another study, a similar dose of ahelical CRF 9 _ 41 applied to the CeA was successful in re-49
Brain Research, 1998
Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical f... more Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the m opioid receptor into the Ž. amygdala results in inhibition of the tail flick TF reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared Ž. Ž. Ž. for microinjection of DAMGO 0.5 mgr0.25 ml into the basolateral amygdala BLA and lidocaine HCl 2.5%r0.4-0.5 ml into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat. q 1998 Elsevier Science B.V.
Nature, 1997
The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primaril... more The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.
Pain, 2000
We have previously shown that activation of kappa opioid receptors within the rostral ventral med... more We have previously shown that activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized rats has an anti-mu opioid analgesic action in male rats. Microinjections of the kappa opioid receptor agonist, U69593, attenuated the increase in tailick latency produced by activation of mu opioid receptors located within the ventrolateral periaqueductal gray. There are sex differences in the pain modulating potency of opioid analgesics, including kappa opioid agonists. In the present study, we examined whether activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized female rats produces an anti-mu opioid analgesic effect similar to that found in males. We found that in the RVM the same dose of kappa opioid receptor agonist that reduces mu receptor-mediated increase in tail-¯ick latency in male rats produces a moderate increase in tail-¯ick latency in female rats. Additionally, we discovered that female rats are signi®cantly more sensitive to the mu opioid agonist, DAMGO, injected into the ventrolateral periaqueductal gray. The results indicate that these two brain structures, which mediate the analgesic effects of opioids, are sexually dimorphic with regard to opioid receptor function.
NeuroReport, 1999
THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid re... more THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the ìopioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[ø] or the DOR 2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[ø] (1.0 ìg) and NTB (5.0 ng) signi®cantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results con®rm and extend previous studies suggesting that PAG ì-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.
Pharmacology Biochemistry and Behavior, 1997
A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, an... more A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.
Neuroscience, 2000
The rostral ventromedial medulla contains three physiologically defined classes of pain-modulatin... more The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the placeconditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the a 1-adrenoceptor agonist methoxamine (50.0 mg in 0.5 ml; to activate ON cells, primarily), combined with local microinjection of the k-opioid receptor agonist U69,593 (0.178 mg in 0.5 ml; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69,593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.
Brain Research, 1998
Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical f... more Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the m opioid receptor into the Ž. amygdala results in inhibition of the tail flick TF reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared Ž. Ž. Ž. for microinjection of DAMGO 0.5 mgr0.25 ml into the basolateral amygdala BLA and lidocaine HCl 2.5%r0.4-0.5 ml into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat. q 1998 Elsevier Science B.V.
NeuroReport, 1993
... Helmstetter, Fred J.; Bellgowan, Patrick S.; Tershner, Sheralee A. Neuroreport: An Internatio... more ... Helmstetter, Fred J.; Bellgowan, Patrick S.; Tershner, Sheralee A. Neuroreport: An International Journal for the Rapid Communication of Research in Neuroscience, Vol 4(5), May 1993, 471-474. doi: 10.1097/00001756-199305000-00002. Abstract. ...
The presentation of an auditory stimulus that signals a noxious event such as foot shock results ... more The presentation of an auditory stimulus that signals a noxious event such as foot shock results in the simultaneous expression of multiple aversive conditional responses (CRs), which include a transient elevation of arterial blood pressure (ABP) and an opioid-mediated form of hypoalgesia. Recent evidence suggests that the neural circuits responsible for the expression of these two aversive responses may overlap. In the present study, rats were trained using a Pavlovian fear conditioning paradigm in which white noise was repeatedly paired with shock. After training, groups of animals received electrolytic lesions centered in the dorsal or ventral periaqueductal gray (PAG) or in the medial or lateral rostra1 medulla. In sham-lesioned animals that were given paired presentations of noise and shock, subsequent presentation of the auditory stimulus caused a significant transient elevation
Pharmacology, Biochemistry and Behavior, Aug 1, 1997
A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, an... more A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.
Neuroscience, Oct 1, 2000
The rostral ventromedial medulla contains three physiologically defined classes of pain-modulatin... more The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the placeconditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the a 1-adrenoceptor agonist methoxamine (50.0 mg in 0.5 ml; to activate ON cells, primarily), combined with local microinjection of the k-opioid receptor agonist U69,593 (0.178 mg in 0.5 ml; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69,593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.
Nature, Sep 1, 1997
The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primaril... more The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.
American Journal of Physiology-renal Physiology, Aug 1, 1991
Evidence that the renal sympathetic nerves have direct effects on renal tubular function suggests... more Evidence that the renal sympathetic nerves have direct effects on renal tubular function suggests that neurogenic mechanisms may play an important role in the daily regulation of sodium balance. We evaluated the influence of the renal nerves on the rate of elevating urinary sodium excretion (UNaV) after a step increase in fixed sodium intake. Conscious rats with innervated (INN) or denervated (DNX) kidneys were placed on low-sodium intake (LNa = 0.3 meq/day) or a normal sodium intake (NNa = 1.0 meq/day) by intravenous infusion. Hourly changes in UNaV were determined 24 h before and 72 h after increasing sodium intake to either NNa or high-sodium intake (HNa = 5.0 meq/day). Switching from LNa to NNa, INN rats increased UNaV within 24 h; however, DNX rats did not begin to increase UNaV until hour 60. Cumulative sodium balance over 72 h was more positive in DNX rats (INN = 1.29 +/- 0.29 meq; DNX = 2.06 +/- 0.21 meq, P less than 0.05). During the LNa-to-HNa switch, both INN and DNX rats increased UNaV equally for 12 h; however, at this time INN rats continued to increase UNaV, whereas DNX rats did not. DNX rats had a net accumulation of 2.54 meq more sodium than INN rats over 72 h. Significant inhibition of plasma renin activity within the first 24 h occurred only in rats receiving the LNa-to-HNa switch in sodium intake, and this response was not different between rats with innervated and denervated kidneys. These data suggest that the renal nerves provide a rapid sodium excretory response to step increases in sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Neuroreport, Oct 1, 1999
THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid re... more THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the ìopioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[ø] or the DOR 2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[ø] (1.0 ìg) and NTB (5.0 ng) signi®cantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results con®rm and extend previous studies suggesting that PAG ì-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.
Psychobiology, Mar 1, 1996
CeA. One study demonstrated that direct application of ahelical CRF 9 _ 41 into the CeA dose-depe... more CeA. One study demonstrated that direct application of ahelical CRF 9 _ 41 into the CeA dose-dependently reversed the heightened emotionality of socially defeated rats (Heinrichs et ai., 1992). In another study, a similar dose of ahelical CRF 9 _ 41 applied to the CeA was successful in re-49
Brain Research, 1998
Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical f... more Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the m opioid receptor into the Ž. amygdala results in inhibition of the tail flick TF reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared Ž. Ž. Ž. for microinjection of DAMGO 0.5 mgr0.25 ml into the basolateral amygdala BLA and lidocaine HCl 2.5%r0.4-0.5 ml into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat. q 1998 Elsevier Science B.V.
Nature, 1997
The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primaril... more The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.
Pain, 2000
We have previously shown that activation of kappa opioid receptors within the rostral ventral med... more We have previously shown that activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized rats has an anti-mu opioid analgesic action in male rats. Microinjections of the kappa opioid receptor agonist, U69593, attenuated the increase in tailick latency produced by activation of mu opioid receptors located within the ventrolateral periaqueductal gray. There are sex differences in the pain modulating potency of opioid analgesics, including kappa opioid agonists. In the present study, we examined whether activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized female rats produces an anti-mu opioid analgesic effect similar to that found in males. We found that in the RVM the same dose of kappa opioid receptor agonist that reduces mu receptor-mediated increase in tail-¯ick latency in male rats produces a moderate increase in tail-¯ick latency in female rats. Additionally, we discovered that female rats are signi®cantly more sensitive to the mu opioid agonist, DAMGO, injected into the ventrolateral periaqueductal gray. The results indicate that these two brain structures, which mediate the analgesic effects of opioids, are sexually dimorphic with regard to opioid receptor function.
NeuroReport, 1999
THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid re... more THE present study tested the hypothesis that endogenous opioid peptides acting at the ä-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the ìopioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[ø] or the DOR 2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[ø] (1.0 ìg) and NTB (5.0 ng) signi®cantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results con®rm and extend previous studies suggesting that PAG ì-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.
Pharmacology Biochemistry and Behavior, 1997
A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, an... more A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.
Neuroscience, 2000
The rostral ventromedial medulla contains three physiologically defined classes of pain-modulatin... more The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the placeconditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the a 1-adrenoceptor agonist methoxamine (50.0 mg in 0.5 ml; to activate ON cells, primarily), combined with local microinjection of the k-opioid receptor agonist U69,593 (0.178 mg in 0.5 ml; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69,593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.
Brain Research, 1998
Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical f... more Ž. Ž. The amygdala, periaqueductal gray PAG , and rostral ventromedial medulla RVM are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the m opioid receptor into the Ž. amygdala results in inhibition of the tail flick TF reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared Ž. Ž. Ž. for microinjection of DAMGO 0.5 mgr0.25 ml into the basolateral amygdala BLA and lidocaine HCl 2.5%r0.4-0.5 ml into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat. q 1998 Elsevier Science B.V.
NeuroReport, 1993
... Helmstetter, Fred J.; Bellgowan, Patrick S.; Tershner, Sheralee A. Neuroreport: An Internatio... more ... Helmstetter, Fred J.; Bellgowan, Patrick S.; Tershner, Sheralee A. Neuroreport: An International Journal for the Rapid Communication of Research in Neuroscience, Vol 4(5), May 1993, 471-474. doi: 10.1097/00001756-199305000-00002. Abstract. ...
The presentation of an auditory stimulus that signals a noxious event such as foot shock results ... more The presentation of an auditory stimulus that signals a noxious event such as foot shock results in the simultaneous expression of multiple aversive conditional responses (CRs), which include a transient elevation of arterial blood pressure (ABP) and an opioid-mediated form of hypoalgesia. Recent evidence suggests that the neural circuits responsible for the expression of these two aversive responses may overlap. In the present study, rats were trained using a Pavlovian fear conditioning paradigm in which white noise was repeatedly paired with shock. After training, groups of animals received electrolytic lesions centered in the dorsal or ventral periaqueductal gray (PAG) or in the medial or lateral rostra1 medulla. In sham-lesioned animals that were given paired presentations of noise and shock, subsequent presentation of the auditory stimulus caused a significant transient elevation