Neonatal bladder inflammation alters activity of adult rat spinal visceral nociceptive neurons.

PURPOSE: This investigation examined the effect of inflammation produced by intravesical zymosan during the neonatal period on spinal dorsal horn neuronal responses to urinary bladder distension (UBD) as adults. METHODS: Female rat pups (P14-P16) were treated with intravesical zymosan or with anesthesia-only. These groups of rats were subdivided forming four groups: half received intravesical zymosan as adults and half received anesthesia-only. One day later, rats were anesthetized, the spinal cord was transected at a cervical level and extracellular single-unit recordings of L6-S1 dorsal horn neurons were obtained. Neurons were classified as Type I--inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II--not inhibited by HNCS--and were characterized for Spontaneous Activity and responses to graded UBD (20-60 mm Hg). RESULTS: 227 spinal dorsal horn neurons excited by UBD were characterized. In rats treated as neonates with anesthesia-only, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following adult intravesical zymosan treatment whereas Type I neurons demonstrated decreased spontaneous and UBD-evoked activity relative to controls. In rats treated as neonates with intravesical zymosan, the spontaneous and UBD-evoked activity of both Type I and Type II neurons increased following adult intravesical zymosan treatment relative to controls. CONCLUSIONS: Neonatal bladder inflammation alters subsequent effects of acute bladder inflammation on spinal dorsal horn neurons excited by UBD such that overall there is greater sensory neuron activation. This may explain the visceral hypersensitivity noted in this model system and suggest that impaired inhibitory systems may be responsible.

Acute bladder inflammation differentially affects rat spinal visceral nociceptive neurons.

The present investigation examined the effect of inflammation produced by intravesical zymosan on spinal dorsal horn neuronal responses to urinary bladder distension (UBD). Extracellular single-unit recordings of neurons excited by UBD were obtained in spinalized female Sprague-Dawley rats. Neurons were classified as Type I-inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II-not inhibited by a HNCS. In Experiment 1-following neuronal characterization, 1% zymosan was infused into the bladder and after 2h spinal units were recharacterized. Control rats received intravesical saline or subcutaneous zymosan. In Experiment 2-rats were pretreated with intravesical zymosan 24h prior to surgical preparation. Control rats received anesthesia only. 137 spinal dorsal horn neurons excited by UBD were characterized. In comparison with controls, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following intravesical zymosan treatment (both Experiments 1 and 2) whereas Type I neurons demonstrated either no change (Experiment 1) or decreased activity (Experiment 2) following bladder inflammation. No significant changes were noted in neuronal activity in control experiments. Inflammation differentially affects subpopulations of spinal dorsal horn neurons excited by UBD that can be differentiated according to the effect of HNCS. This results in an altered pattern of spinal sensory transmission that may serve as the mechanism for the generation of visceral nociception.

Jejunal or portal vein infusions of lipids increase hepatic vagal afferent activity.

Jejunal infusions of linoleic acid, corn oil, or caprylic acid significantly increased hepatic vagal afferent activity, whereas saline infusions were ineffective. The magnitude of response was greatest with either linoleic acid or corn oil. Hepatic portal infusions of linoleic acid, Liposyn II, or caprylic acid significantly increased hepatic vagal afferent activity, whereas 5% albumin/phosphate buffer vehicle was ineffective. The magnitude of response was greatest with either linoleic acid or Liposyn II. These data show that either jejunal or portal infusions of lipids increase activity of hepatic vagal afferents and could potentially serve as a complementary and/or alternative substrate to celiac vagal afferents in mediating the effects of jejunal infusions of lipids in suppressing food intake.

Celiac vagotomy reduces suppression of feeding by jejunal fatty acid infusions.

We investigated the role of the celiac branch of the vagus nerve in suppression of food intake produced by jejunal fatty acids infusions. Following selective celiac vagotomy or sham surgery, adult, male Sprague-Dawley rats received 7 h infusions of linoleic acid or saline through indwelling jejunal catheters on four consecutive days. Although linoleic acid still produced significant suppression of intake in rats with celiac vagotomy, it was less effective in these animals than in controls. The temporal pattern of results suggested that celiac afferent fibers are involved in mediating both pre- and postabsorptive effects of infused fatty acids.

The effect of spinal and systemic administration of indomethacin on zymosan-induced edema, mechanical hyperalgesia, and thermal hyperalgesia.

Pretreatment with intraperitoneal (i.p.) indomethacin was used to determine whether indomethacin preferentially affected the development of edema and hyperalgesia to thermal and mechanical stimuli produced by injection of zymosan in the ispsilateral hindpaw of the rat. Indomethacin also was delivered intrathecally (i.t.) either 30 minutes before or 4 hours after intraplantar zymosan to determine whether spinal prostaglandin production was important for the induction and/or maintenance of hyperalgesia. Zymosan alone produced a robust edema, a monophasic mechanical hyperalgesia, and a biphasic thermal hyperalgesia in the ipsilateral hindpaw. Systemic administration of indomethacin reduced zymosan-induced edema and increased thermal and mechanical response thresholds in the zymosan-injected paw. Systemic indomethacin did not affect thermal withdrawal response thresholds in the uninjected contralateral hindpaw of zymosan-treated rats, but significantly increased mechanical withdrawal thresholds of the uninjected contralateral paw of zymosan-treated rats. i.t. administration of indomethacin before the induction of hyperalgesia attenuated the development of zymosan-induced mechanical hyperalgesia, but did not affect the development of either zymosan-induced edema or thermal hyperalgesia. Once hyperalgesia was established, i.t. indomethacin also attenuated the mechanical hyperalgesia whereas it had no effect on thermal hyperalgesia or edema. These data suggest that peripheral, but not spinal prostaglandins contribute to the edema and development of thermal hyperalgesia produced by zymosan. In contrast, spinal prostaglandins contribute to the development and maintenance of mechanical hyperalgesia.

Effects of glutamate receptor antagonists on spinal dorsal horn neurons during zymosan-induced inflammation in rats.

These experiments examined the effects of spinal administration of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV), the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), or the metabotropic glutamate receptor antagonist DL-2-amino-3-phosphonoproprionic acid (AP3) on responses of spinal dorsal horn neurons evoked by thermal and mechanical stimuli applied to the rat hindpaw in either an inflamed or noninflamed state. Administration of APV, DNQX, or AP3 decreased heat-evoked neuronal discharges of wide dynamic range (WDR) neurons that were previously augmented by zymosan-induced inflammation. APV and DNQX also decreased heat-evoked discharges of WDR neurons that were previously unaffected by saline injection. Administration of either APV or DNQX, but not AP3, decreased heat-evoked neuronal discharges of nociceptive-specific (NS) neurons in both zymosan- and saline-injected rats. These data suggest that NMDA and non-NMDA receptors contribute to spinal processing of thermal stimuli in both the inflamed and noninflamed state, whereas metabotropic glutamate receptors might serve a role that is unique to WDR neurons in the inflamed state. Only DNQX consistently increased mechanical response thresholds and decreased slopes of the mechanical stimulus response functions (SRFs) of NS and WDR neurons, but this effect was observed in both inflamed and noninflamed states. These data suggest that spinal processing of mechanical stimuli is preferentially mediated by glutamate acting at non-NMDA receptors in either the inflamed or noninflamed state.

Low intensity vagal nerve stimulation lowers human thermal pain thresholds.

The effect of vagal nerve stimulation (VNS) on thermal pain sensation was studied in eight subjects who had vagal nerve stimulators surgically implanted for purposes of seizure control. Prior to their involvement in the study, all subjects had the intensity of their VNS (30 Hz, 0.5 ms, 1.0-2.75 mA) adjusted upwards until achieving their desired clinical effect of reduced seizures. Thermal pain thresholds were determined using a Medoc TSA-2001 with a thermode applied to the skin of the forearm. During VNS at settings 100% of those used clinically to control their seizures, subjects showed a statistically significant decrease in their thermal pain threshold of 1.1+/-0.4 degrees C. Acute effects of graded VNS on thermal pain thresholds were determined in seven of the subjects after cessation of chronic VNS. Two thermal threshold measurements were obtained while the subject received sham stimulation (0 mA intensity), during tactile control stimulation and during 30 s of VNS at intensities approximately 33, 66 and 100% of the settings utilized to control their seizures. Tactile control stimulation was provided by electrical stimulation of the skin of the ankle with the intensity adjusted by the patient to match the intensity of any sensations felt in the neck during VNS. Subjects were not aware of the settings employed. Their stimulator was adjusted with each trial and an ascending/descending ordering of intensity was utilized with an inter-trial interval of 2 min. Thermal pain thresholds were significantly decreased in relation to tactile control stimulation at all intensities of VNS tested with the greatest effect occurring at the 66% level. Subjects were also monitored non-invasively and hemodynamic responses to VNS were determined. No significant alterations in hemodynamic variables were observed. The findings of this human study are consistent with experiments in non-human animals which demonstrate a pro-nociceptive effect of low intensity VNS.

Suppression of food intake, body weight, and body fat by jejunal fatty acid infusions.

Three experiments investigated effects of jejunal lipid infusions given on 4 or 21 consecutive days in adult, male Sprague-Dawley rats. In experiment 1, 7-h infusions of linoleic or oleic acid (0.2 ml/h for 7 h; total load = 11.5 kcal) on 4 consecutive days reduced total intake (ad libitum consumption of the liquid diet Boost, Mead Johnson, plus load) by approximately 15% and decreased weight gain compared with 4-day tests with saline administration. In experiment 2, linoleic acid at 0.1 ml/h for 7 h (5.7 kcal) was ineffective, whereas the same load delivered in 3.5 h produced effects similar in magnitude to those in the first experiment. In experiment 3, jejunal infusions of linoleic acid (0.2 ml/h for 7 h) on 21 consecutive days reduced mean total intake by 16%, body weight by 10%, and carcass fat by 48% compared with controls receiving saline. The net decrease in caloric intake may reflect the combined activation of pre- and postabsorptive mechanisms, and it suggests a possible treatment for obesity.

Responses of celiac and cervical vagal afferents to infusions of lipids in the jejunum or ileum of the rat.

Multiunit celiac and single-unit cervical recordings of vagal afferents were performed before and during infusions of fatty acids, triglycerides, or saline into either the ileum or jejunum of the rat. In multiunit recordings, lipids increased activity of vagal afferents to a greater extent than saline. The greatest increases in vagal afferent activity resulted from infusions of linoleic acid, conjugated linoleic acid, or oleic acid. The triglycerides, corn oil or Intralipid, were less effective than the fatty acids in affecting vagal afferent activity. Ileal pretreatment with the hydrophobic surfactant Pluronic L-81 significantly attenuated the response of celiac vagal afferents to ileal infusion of linoleic acid. Single-unit recordings of cervical vagal afferents supported the multiunit data in showing lipid-induced increased vagal afferent activity in approximately 50% of ileal units sampled and 100% of a limited number of jejunal units sampled. These data demonstrate that free fatty acids can activate ileal and jejunal vagal afferents in the rat, and this effect can be attenuated by pretreatment with a chylomicron inhibitor. These data are consistent with the view that lipid-induced activation of vagal afferents could be a potential substrate for the inhibitory effects of intestinal lipids on gastrointestinal function, food intake, and body weight gain.

Responses of primary afferents and spinal dorsal horn neurons to thermal and mechanical stimuli before and during zymosan-induced inflammation of the rat hindpaw.

Intraplantar administration of zymosan produces inflammation and results in behavioral evidence of hyperalgesia to mechanical and thermal stimuli in the rat. In the present studies, responses of primary afferents and spinal dorsal horn neurons to mechanical and thermal stimuli were examined before and during zymosan-induced inflammation of the hindpaw. In tests of responses of primary afferents to mechanical stimuli, group mean mechanical response thresholds of C-mechanonociceptor (CMN) units significantly decreased after zymosan administration. The group mean mechanical response thresholds of low threshold mechanoreceptor (LTM) units, A-mechanoheat (AMH) units, high threshold mechanoreceptor (HTM) units, and C-mechanoheat (CMH) units showed either no change or were increased significantly by intraplantar administration of zymosan. The group mean total discharges evoked during the 10 s mechanical stimulus were significantly increased after zymosan administration in CMN units. The group mean total discharges were either significantly decreased or unchanged in LTM, AMH, HTM, and CMH units. In tests of responses of spinal dorsal horn neurons to mechanical stimuli, the group mean mechanical response threshold of nociceptive specific (NS) units decreased significantly 1 h following administration of zymosan, whereas no significant changes occurred in the mechanical response thresholds of wide dynamic range (WDR) neurons in zymosan-injected rats, WDR neurons in saline-injected rats, or NS neurons in saline-injected rats. The group mean total discharges of only NS neurons were significantly increased during the 10 s mechanical stimulus 3 and 4 h after zymosan administration. In tests of responses of primary afferents to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in group mean response thresholds of CMH units and significant increases in group mean response thresholds of AMH units. The group mean total discharges of CMH units was either unchanged or significantly increased during thermal stimuli depending on both the time of testing and the temperature of the test stimulus. The group mean total number of discharges of AMH units was significantly decreased during tests of all thermal stimuli. In tests of responses of spinal dorsal horn neurons to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in thermal response thresholds of both WDR and NS units of zymosan-injected rats, but no changes in WDR and NS units of saline-injected rats. The group mean total discharges evoked by the 15 s thermal stimuli also increased significantly in both WDR and NS units after zymosan administration. Zymosan administration resulted in increased background activity only in CMH units. These increases occurred immediately following the injection and dissipated by the first hourly test period. Significant changes in background discharges of both WDR and NS units occurred at some hourly test intervals following administration of zymosan, but these changes were not consistent with respect to either unit type or modality of the test stimulus. These data suggest that the zymosan-induced hyperalgesia to mechanical stimuli observed in behavioral studies reflects decreases in response thresholds of peripheral CMN units and spinal NS neurons. Hyperalgesia to thermal stimuli reflects decreases in response thresholds of peripheral CMH units, spinal WDR neurons, and spinal NS neurons. These data support the view that different physiological substrates mediate hyperalgesia to either thermal or mechanical stimuli following intraplantar administration of zymosan.

CCK-8 activates hepatic vagal C-fiber afferents.

Intravenous administration of 2 micrograms/kg CCK-8 increased the single unit activity of 54% of hepatic vagal afferent fibers. Conduction velocity tests indicated that all of these units were C fibers. The increase in hepatic vagal activity produced by CCK-8 was significantly reduced by i.v. administration of 200 micrograms/kg of the CCKA receptor antagonist devazepide. Control comparisons indicated that this reduction was not an artifact of tachyphylaxis resulting from repeated administration of CCK-8. Further, the inability of pretreatment with atropine and hexamethonium to reduce the increases in hepatic vagal activity produced by CCK-8 suggests that the latter effect was not secondary to changes in gastrointestinal motor function. These outcomes demonstrate that activation of CCKA receptors by CCK-8 increases hepatic vagal afferent activity and support the view that the duodenal satiety action of CCK is mediated by the hepatic branch.

Responses of on and off cells in the rostral ventral medulla to stimulation of vagal afferents and changes in mean arterial blood pressure in intact and cardiopulmonary deafferented rats.

The relationships between mean arterial blood pressure (MAP) and the activity of putative pain modulatory neurons of the rostroventral medulla (ON and OFF cells) were determined in intact and cardiopulmonary deafferented rats. A total of 173 neurons were recorded from 97 rats as follows: 32 ON cells and 25 OFF cells from 39 intact rats; 32 ON cells and 20 OFF cells from 24 rats with bilateral sino-aortic deafferentation (SAD); 12 ON cells and 20 OFF cells from 19 rats with bilateral cervical vagotomy (CVAG); and 20 ON cells and 12 OFF cells from 15 rats with both SAD and CVAG. ON and OFF cells showed spontaneous fluctuations in activity such that ON cell activity was negatively correlated with MAP whereas OFF cell activity was positively correlated with MAP under conditions of no applied stimuli. These correlations were present in both intact and cardiopulmonary deafferented rats. Further, experimentally induced increases in MAP decreased ON cell activity and increased OFF cell activity in intact rats, but not in rats with SAD, CVAG, or the combination of SAD and CVAG. Experimentally induced decreases in MAP decreased OFF cell activity in intact rats and rats with CVAG, but not in rats with SAD or the combination of SAD and CVAG. These findings indicate that ON and OFF cells are modulated by baroreceptor activity, but baroreceptor input is not necessary for the spontaneous fluctuations in ON and OFF cell activity. Electrical stimulation of vagal afferents (VAS) inhibited 60% of the OFF cells studied, excited 4%, and produced biphasic effects consisting of excitation at low intensities and inhibition at greater intensities in 28% of all OFF cells. In general, VAS excited the majority of the ON cells studied, although there were significant differences between effects in intact and cardiopulmonary deafferented rats. Greater intensities of VAS that inhibited OFF cells and excited ON cells also inhibited the tail flick. Thus, inhibition of OFF cells and excitation of ON cells was correlated with antinociception. The effects of intravenous (i.v.) administration of 1.0 mg/kg morphine on neuronal activity did not differ between intact and cardiopulmonary deafferented rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Neural substrates of pain and analgesia.

The anatomic, physiologic, and chemical properties of systems involved in encoding and transmitting nociceptive input provide a basis for understanding the experience of pain. Moreover, the fact that these nociceptive systems can be modulated by other neural and humoral systems provides explanations for pain inhibition, pain enhancement, and the variability observed with various types of pain. Neural plasticity and permanent restructuring of these systems following injury also are likely to contribute to short- and long-term changes in the experience of pain. In summary, our understanding of acute and chronic pain has been significantly advanced through investigations of the neural substrates of pain and analgesia.

Changes in nociception, arterial blood pressure and heart rate produced by intravenous morphine in the conscious rat.

The present study shows that intravenous (i.v.) administration of morphine produces dose-dependent increases in tail flick and hot plate latencies in conscious rats. I.v. morphine also decreased heart rate, but had no significant effects on arterial blood pressure. Transection of the right vagus at the cervical level or pre-treatment with the peripherally acting opioid receptor antagonist naloxone methobromide attenuated the increased tail flick latency produced by either 1.75 or 2.5 mg/kg morphine. In addition, either right vagotomy or naloxone methobromide attenuated the increased hot plate latency produced by 1.75 mg/kg of morphine but not by 2.5 mg/kg of morphine. Following pre-treatment with naloxone methobromide, 1.75 and 2.5 mg/kg of morphine produced a small pressor response 1-3 min after injection. The bradycardia produced by 1.75 mg/kg of morphine was attenuated by naloxone methobromide, but not by right vagotomy. The bradycardia produced by 2.5 mg/kg of morphine was attenuated by either naloxone methobromide or vagotomy. These data obtained in the conscious rat are similar to previous reports using pentobarbital-anesthetized rats except for the following: (i) the dose-response function for inhibition of the tail flick was shifted to the right in conscious rats, (ii) the depressor response to morphine observed in anesthetized rats was attenuated in conscious rats, (iii) following naloxone methobromide, but not unilateral vagotomy, i.v. morphine produced a pressor response in the conscious rat, and (iv) unilateral vagotomy was not as effective in attenuating the antinociception and bradycardia in conscious rats as bilateral vagotomy is in pentobarbital-anesthetized rats.

Vagal afferent stimulation-produced effects on nociception in capsaicin-treated rats.

1. The effects of electrical stimulation of cervical vagal afferent fibers on the nociceptive tail-flick (TF) reflex and responses of spinal dorsal horn neurons to noxious cutaneous stimulation were studied in adult rats treated as neonates with either capsaicin or vehicle. 2. Vagal afferent stimulation (VAS) produced biphasic, intensity-dependent effects on the TF reflex in vehicle-treated and untreated control rats. The TF reflex was facilitated in both groups of rats at lesser intensities of VAS (2.5-50 microA) and fully inhibited at greater intensities of VAS (50-100 microA). In contrast, biphasic effects of VAS on the TF reflex generally were not produced in rats treated as neonates with capsaicin. Facilitation of the TF reflex was produced in these rats by lesser intensities of VAS as well as by typically "inhibitory" intensities of VAS; the TF reflex was never inhibited in 6/12 rats, even at the greatest intensity of VAS tested (1,000 microA). When the TF reflex was inhibited by VAS in capsaicin-treated rats, the intensities required were significantly greater than those required in vehicle-treated or untreated rats. 3. In electrophysiological experiments, 77 neurons were recorded in the lumbar spinal dorsal horn of pentobarbital sodium-anesthetized, paralyzed rats treated as neonates with either vehicle or capsaicin. The neurons had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind foot, and all responded to mechanical stimuli of both nonnoxious and noxious intensities; 16/77 neurons also responded to noxious thermal stimulation. In vehicle-treated rats, nociceptive responses of 50% of 30 units studied were biphasically modulated by VAS, 33% were only inhibited, and 17% were only facilitated by VAS at the intensities tested (5-500 microA). In capsaicin-treated rats, nociceptive responses of 32% of 47 units studied were biphasically modulated by VAS, 15% were only inhibited, and 34% were only facilitated by VAS at the intensities tested (5-500 microA). In addition, nociceptive responses of neurons facilitated at lesser intensities of VAS and not affected at greater intensities of VAS were observed in capsaicin-treated rats (19% of the 47-unit sample). Overall, the proportion of the neuronal sample inhibited by VAS was less, and the proportion of the sample facilitated by VAS was greater in capsaicin-treated rats compared with vehicle-treated rats. 4. The efficacy of the capsaicin treatment was evaluated immunocytochemically.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of specific opioid agonists and antagonists to delineate the vagally mediated antinociceptive and cardiovascular effects of intravenous morphine.

Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cervical vagotomy (CVAG) to delineate the vagal afferent/opioid-mediated components of these effects. I.v. administration of DAGO in intact rats produced a dose-dependent inhibition of the TF reflex, depressor response, and bradycardia virtually identical to those produced by i.v. morphine. All of these effects of either i.v. DAGO or i.v. morphine were significantly attenuated by either bilateral CVAG or pre-treatment with the mu 2 opioid receptor antagonist beta-FNA. Pre-treatment with the mu 1 opioid receptor antagonist naloxonazine affected i.v. DAGO-induced inhibition of the TF reflex and bradycardia, but had no significant effects on i.v. morphine-produced responses. I.v. administration of DPDPE produced a dose-dependent pressor response, but had no marked effects on the either the TF reflex or heart rate (HR). The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex. The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone. These studies suggest that the vagal afferent-mediated antinociceptive and cardiovascular effects of i.v. morphine are primarily mediated by interactions with low affinity mu 2 opioid receptors.

Electrical stimulation of the subdiaphragmatic vagus in rats: inhibition of heat-evoked responses of spinal dorsal horn neurons and central substrates mediating inhibition of the nociceptive tail flick reflex.

Electrical stimulation of the subdiaphragmatic branch of the vagus nerve (SDVAS) inhibits the nociceptive tail flick (TF) reflex. The present experiments examined (1) the central substrates mediating SDVAS-produced inhibition of the TF reflex and (2) the effects of SDVAS on either background or noxious heat-evoked responses of spinal dorsal horn neurons. Microinjections of ibotenic acid in the ipsilateral nucleus tractus solitarius (NTS), nucleus raphe magnus (NRM), or bilateral locus coeruleus/subcoeruleus (LC/SC) significantly increased the intensity of SDVAS required to inhibit the TF reflex in lightly anesthetized rats. In studies of class-2 spinal dorsal horn neurons, SDVAS produced significant intensity-dependent inhibition of noxious heat-evoked responses of 17/25 (68%) units, facilitation of 4/25 (16%) units, and no effect on 4/25 (16%) units. In studies of class-3 spinal dorsal horn neurons, SDVAS produced significant intensity-dependent inhibition of noxious heat-evoked responses of 8/9 (89%) units. Noxious heat-evoked responses of 1/9 (11%) unit were facilitated by SDVAS. In general, the background activity of either class-2 or class-3 units was not significantly affected by SDVAS. SDVAS produced a significant rightward, parallel shift in the stimulus response function (SRF) of class-2 neurons to noxious, graded heat stimuli ranging from 40 to 52 degrees C, while SDVAS produced a significant increase in the threshold and a significant reduction in the slope of the SRF of class-3 neurons. These data indicate that SDVAS generally inhibits noxious heat-evoked responses of lumbosacral spinal dorsal horn neurons in the rat, but does not significantly affect background activity of the same neurons. Furthermore, the inhibition of the TF reflex produced by SDVAS depends on central relays in the ipsilateral NTS, NRM, and bilateral LC/SC.

Intravenous morphine-induced activation of vagal afferents: peripheral, spinal, and CNS substrates mediating inhibition of spinal nociception and cardiovascular responses.

1. Intravenous administration of 1.0 mg/kg of morphine produces inhibition of the nociceptive tail-flick (TF) reflex, hypotension, and bradycardia in the pentobarbital-anesthetized rat. The present experiments examined peripheral, spinal, and supraspinal relays for inhibition of the TF reflex and cardiovascular responses produced by morphine (1.0 mg/kg iv) in the pentobarbital-anesthetized rat using 1) bilateral cervical vagotomy, 2) spinal cold block or mechanical lesions of the dorsolateral funiculi (DLFs), or 3) nonselective local anesthesia or soma-selective lesions of specific CNS regions. Intravenous morphine-induced inhibition of responses of unidentified, ascending, and spinothalamic tract (STT) lumbosacral spinal dorsal horn neurons to noxious heating of the hindpaw were also examined in intact and bilateral cervical vagotomized rats. 2. Bilateral cervical vagotomy significantly attenuated inhibition of the TF reflex and bradycardia produced by intravenous administration of morphine. Bilateral cervical vagogtomy changed the normal depressor response produced by morphine into a sustained pressor response. Inhibition of the TF reflex in intact rats was not due to changes in tail temperature. 3. Spinal cold block significantly attenuated inhibition of the TF reflex, the depressor response, and the bradycardia produced by intravenous administration of morphine. However, bilateral mechanical transections of the DLFs failed to significantly affect either inhibition of the TF reflex or cardiovascular responses produced by this dose of intravenous morphine. 4. Microinjection of either lidocaine or ibotenic acid into the nuclei tracti solitarii (NTS), rostromedial medulla (RMM), or ventrolateral pontine tegmentum (VLPT) attenuated morphine-induced inhibition of the TF reflex. Similar microinjections into either the periaqueductal gray (PAG) or the dorsolateral pons (DLP) failed to affect morphine-induced inhibition of the TF reflex. 5. Microinjection of either lidocaine or ibotenic acid into the NTS, RMM, VLPT, DLP, or rostral ventrolateral medulla (RVLM) attenuated the depressor response produced by morphine, although baseline arterial blood pressure (ABP) was affected by ibotenic acid microinjections in the DLP. In all these cases, the microinjections failed to reveal a sustained pressor response as was observed with bilateral cervical vagotomy. Similar microinjections into the PAG failed to affect the depressor response produced by morphine. 6. The lidocaine and ibotenic acid microinjection treatments also showed that the bradycardic response produced by morphine depends on the integrity of the NTS, RMM, RVLM, and possibly the DLP, but not the PAG or VLPT.(ABSTRACT TRUNCATED AT 400 WORDS)

Vagal afferent modulation of nociception.

Chemical, electrical or physiological activation of cardiopulmonary vagal (cervical, thoracic or cardiac), diaphragmatic vagal (DVAG) or subdiaphragmatic vagal (SDVAG) afferents can result in either facilitation or inhibition of nociception in some species. In the rat, these effects depend upon vagal afferent input to the NTS and subsequent CNS relays, primarily in the NRM and ventral LC/SC, although specific relay nuclei vary as a function of the vagal challenge stimulus. Spinal pathways and neurotransmitters have been identified for vagally mediated effects on nociception and consistently implicate the involvement of descending 5-HT and noradrenergic systems, as well as intrinsic spinal opioid receptors. Species differences may exist with respect to both the effects of DVAG and SDVAG afferents on nociception and the efficacy of vagal afferents to modulate nociception. However, it is also possible that such differences reflect the modality of noxious input (e.g., visceral versus cutaneous), the type of neuronal activity investigated (e.g., resting versus noxious-evoked), spinal location of recording (e.g., thoracic versus lumbosacral) and/or parameters of stimulation. It is also possible that activation of some vagal afferents is aversive, but whether this contributes to changes in nociception produced by vagal activation has not clearly been established. Finally, the vagal-nociceptive networks described in this review provide a fertile area for future study. These networks can provide an understanding of physiological and pathophysiological peripheral events that affect nociception.