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There is considerable evidence that on the anterior surface of the heart (which is usually supplied by the left anterior descending and the proximal part of the left circumflex coronary arteries), sympathetic efferent reflexes characterized by tachycardia and/or hypertension predominate following experimental or pathological perturbations. These cardiovascular reflexes are accompanied by an increase in presumed nociceptive afferent traffic and, in pathological condition, by pain. In these experiments, there is generally no effect of vagotomy on afferent nerve traffic, and lower cervical and upper thoracic sympathectomies help provide relief from angina. On the other hand, experimental or pathological perturbations involving the inferior-posterior surface of the heart (supplied by the right and distal parts of the left circumflex coronary arteries), are characterized by vagal efferent reflexes, resulting in bradycardia and/or hypotension. These reflexes are accompanied by an increase in vagal afferent nerve traffic and, in pathological conditions, by pain. In these experiments, vagotomy generally abolishes such cardiovascular reflexes, and lower cervical and upper thoracic sympathectomies are not effective in the relief from angina. Although cardiac sympathetic afferents are unquestionably involved in the central transmission of nociceptive information from the heart, it is also likely that there is a contributing role from the vagus in cardiac pain. It is important experimentally to understand the natural stimulus that gives rise to angina. In the clinical situation, a decrease in coronary blood flow or an increase in the metabolic demands of the myocardium due to increased work are obvious precipitating factors which lead to myocardial ischemia. In the experimental situation, occlusion of the coronary arteries is often used as a stimulus which mimics myocardial ischemia. As people who frequently experience angina have varying degrees of coronary artery disease, it is difficult to accept that the state of the coronary arteries of the normal experimental animal bear any resemblance to the state of the coronary arteries under pathological conditions. That is, the gain of homeostatic reflexes, the basal concentrations of neuroactive substances in the plasma, the myocardium and the afferent terminals, the excitability of the afferents, access of chemical mediators (e.g. bradykinin, 5-HT, adenosine, histamine, prostaglandins, potassium, lactate), to afferents, and the overall function of the animal are all significantly different. We have no idea how control mechanisms have been altered in the person with severe coronary artery disease compared to the normal patient or the "normal" experimental animal.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical investigations have suggested a synergistic interaction between the analgesic effects of intrathecal opioids and local anesthetics; however, basic pharmacologic evidence for this observation has not been reported. Therefore, the authors have used models of visceral and somatic nociception to quantify the interaction between intrathecal morphine and lidocaine in a crossover study of 24 rats in four equal groups. Combinations of morphine and lidocaine were administered separately, corresponding to time of peak effect for each drug. Colorectal distention, as a noxious visceral stimulus, was applied to two groups while cardiovascular and visceromotor responses, respectively, were recorded. A third group received hot plate testing as a somatic nociceptive stimulus. Intrathecal morphine and lidocaine both attenuated the cardiovascular and visceromotor responses to colorectal distention and increased hot plate latencies in a dose- and time-dependent manner. With the use of isobolographic analysis, the coadministration of morphine and lidocaine demonstrated a synergistic, supraadditive interaction during visceral nociception (P less than 0.001) and somatic nociception (P less than 0.005). In a fourth group, motor function was evaluated by an inclined screen method. Intrathecal lidocaine in the dosage range tested during isobolographic analysis revealed no motor deficits. These data clearly demonstrate antinociceptive synergy between intrathecal morphine and lidocaine during visceral and somatic nociception at dosages that do not impair motor function.

In 16-week-old Sprague-Dawley rats lightly anesthetized with pentobarbital, 5-HT (3-96 micrograms/kg, i.v.; n = 6) produced distinct pseudaffective responses and a dose-dependent (slope = 17.2 +/- 6.8 s/log10 dose) inhibition of the tail-flick (TF) reflex (ED50 = 32.6 +/- 9.2 micrograms/kg). In the same rats, a 1:1 combination of alpha-methyl 5-HT (a 5-HT2, receptor selective agonist) and 2-methyl 5-HT (a 5-HT3 receptor selective agonist) (3-192 micrograms/kg, i.v.), produced the same profile of pseudaffective responses and also resulted in a dose-dependent (slope = 34.0 +/- 7.0 s/log10 dose) inhibition of the TF reflex (ED50 = 88.4 +/- 20.5 micrograms/kg). In contrast, administration of alpha-methyl 5-HT (3-192 micrograms/kg, i.v.) or 2-methyl 5-HT (3-192 micrograms/kg, i.v.) alone did not produce any pseudaffective responses or any change in TF latency from baseline. In conscious 16-week-old male Sprague-Dawley rats, administration of 5-HT (48 micrograms/kg, i.v.; n = 5), or a 1:1 combination of alpha-methyl 5-HT and 2-methyl 5-HT (total dose = 120 micrograms/kg, i.v.; n = 5), resulted in a passive avoidance behavior assessed in a step-down paradigm (slopes = 139.7 +/- 58.2 and 154.9 +/- 63.9 s/trial, respectively), and the same profile of distinct pseudaffective responses exhibited by the lightly pentobarbital-anesthetized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

'Noxious' stimuli are pain-producing stimuli and have been traditionally defined as tissue damaging. This definition is not valid for visceral stimuli. Hence, behavioral definitions are needed. Awake, unanesthetized rats learned to passively avoid colorectal distension. The rate of acquisition increased as a function of the distending pressure. Two manipulations, intrathecal morphine and neonatal treatment with capsaicin, attenuated acquisition of avoidance behavior whereas the production of colorectal inflammation using turpentine enhanced acquisition of this behavior. These findings are consistent with the hypothesis that aversion to the stimulus is due to the 'noxious' nature of the stimulus.

We have recently identified a polysynaptic pathway traversing discrete regions of the hypothalamus, midbrain, and medulla, along which site-specific electrical and chemical activation produces coronary vasoconstriction as part of a sympathoexcitatory response. We tested for the potential functional significance of this pathway by examining the hypothesis that a medullary component is involved in carotid baroreflex induced coronary vasoconstriction. Coronary flow velocity was measured with a Doppler probe in anesthetized cats. Following vagotomy and propranolol, bilateral carotid occlusion produced an increase in mean arterial pressure (56 +/- 14%, means +/- S.E.M.) and in coronary vascular resistance (51 +/- 13%) which was greater than that (29 +/- 6%) expected from the concurrent rise in arterial pressure during aortic constriction. Bilateral microinjections of lidocaine into the medullary lateral reticular formation attenuated the reflex increase in pressure (11 +/- 2%) and virtually abolished the rise (8 +/- 2%) in coronary resistance. After one hour recovery, carotid occlusion again increased aortic pressure (56 +/- 13%) and coronary vascular resistance (47 +/- 15%). Microinjections of lidocaine outside this medullary region did not impair the coronary vasoconstrictor response to carotid occlusion. We conclude that the medullary lateral reticular formation contains neural elements which participate in baroreflex-induced changes in arterial pressure and coronary vascular resistance. Components of the previously described central coronary vasoconstrictor pathway may play a role in pathophysiological conditions associated with increased coronary vasomotor tone.

The present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.

The intrathecal (i.t.) coadministration of sub-antinociceptive doses of clonidine, an alpha 2-adrenoceptor agonist, with DOI or RU-24969 (5-HT2 or 5-HT1B receptor agonists, respectively) produced dose-dependent supra-additive antinociceptive effects in a model of visceral pain. The enhanced attenuation of responses to noxious colorectal distension produced by the coadministration of these drugs is evidenced by significant leftward shifts in the dose-response curves as compared to those of each drug alone and by isobolographic analysis. The supra-additive antinociceptive effects produced following the i.t. coadministration of clonidine with RU-24969 were antagonized by i.t. pretreatment with phentolamine; the coadministration of phentolamine with methysergide produced no greater antagonism of effects. The supra-additive antinociceptive effects produced by i.t. coadministration of clonidine with DOI were antagonized by i.t. pretreatment with methysergide; the coadministration of methysergide with yohimbine produced no greater antagonism of effects. These data suggest that receptors acted upon by descending bulbospinal neurons interact to modulate the rostrad transmission of visceral nociceptive transmission.

1. Nocigenic inhibition is the inhibition of neural, behavioral, or reflex responses to a nociceptive test stimulus produced by another, conditioning, nociceptive stimulus. The present study examines whether a natural noxious visceral stimulus, colorectal distension, used as a conditioning stimulus would inhibit neuronal or reflex responses to noxious cutaneous stimuli. Segmental effects of colorectal distension have been previously characterized; hence conditioning effects of colorectal distension on stimuli applied at sites distant (heterosegmental effects) and adjacent (perisegmental effects) to those areas of the spinal cord that receive the greatest afferent input from the colon were examined. The conditioning effects of colorectal distension were compared with those of noxious pinch. 2. Heterosegmental effects of colorectal distension were studied in 129 neurons located in the area of the trigeminal nucleus caudalis and cervical spinal dorsal horn. Steady-state activity (spontaneous activity or activity evoked by sustained pressure) of 106 of 129 trigeminal-cervical dorsal horn neurons was inhibited by both noxious colorectal distension (100 mmHg, 20 s) and noxious pinch of the tail; all neurons inhibited by colorectal distension were also inhibited by noxious pinch. Inhibition was graded with the intensity of the distending stimulus. The class 2-class 3 classification system (neurons excited by nonnoxious and noxious or only by noxious cutaneous stimuli, respectively) was roughly predictive of susceptibility to nocigenic inhibition, because 74 of 75 class 2 neurons tested were inhibited by noxious colorectal distension or noxious pinch and only 32 of 54 class 3 neurons were similarly inhibited. Five neurons were excited by colorectal distension, all of which were class 3 neurons. 3. Perisegmental effects of colorectal distension were observed in 100 L3-L5 spinal dorsal horn neurons. The spontaneous activities and responses during noxious test heating of the glabrous skin of the hindpaw of these neurons were affected in the same way by noxious (conditioning) colorectal distension. All neurons inhibited by colorectal distension (51 class 2 and 8 class 3 neurons) were also inhibited by noxious pinch of the nose or forepaw. The magnitude of the nocigenic inhibition of responses during heating of the hindpaw was graded with the intensity and duration of the noxious conditioning colorectal distension, was a function of the number of preceding distensions given to the rat, and outlasted the distending stimulus. Conditioning colorectal distension also produced a parallel shift to the right in stimulus-response functions relating responses of neurons to the intensity of the noxious test stimulus (42-50 degrees C).(ABSTRACT TRUNCATED AT 400 WORDS)

1. Numerous studies have demonstrated that neural, behavioral, and reflex responses to a nociceptive test stimulus are inhibited by conditioning nociceptive stimuli; this inhibition has supraspinal, intraspinal, and segmental components. The general phenomenon is defined here as nocigenic inhibition. The present study of nocigenic inhibition documents that noxious cutaneous pinch and heat, used as conditioning stimuli, inhibit neuronal and reflex responses evoked by a noxious visceral stimulus, colorectal distension. 2. A total of 196 dorsal horn neurons were examined: 110 were short latency-abrupt (SL-A) neurons that were excited at short latency by colorectal distension and returned to baseline activity abruptly after termination of the distending stimulus, and 86 were short latency-sustained (SL-S) neurons that also were excited by colorectal distension at short latency, but demonstrated after-discharges for 4-240 s after termination of the distending stimulus. All SL-A and SL-S neurons studied had convergent cutaneous receptive fields. 3. The spontaneous activities of 100% of the 110 SL-A neurons tested were inhibited by greater than 25% by noxious pinch in sites distant from their convergent cutaneous receptive fields. In both anesthetized, intact, and spinalized rats, noxious conditioning pinch or noxious conditioning heat significantly reduced responses of SL-A neurons during noxious test colorectal distension. The magnitude of this nocigenic inhibition was graded with the intensity of the noxious conditioning stimulus. Noxious conditioning tail heating produced a parallel shift to the right in stimulus-response functions relating neuronal responses to the intensity of colorectal distension (20-100 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitation of the nociceptive tail flick (TF) reflex produced by low intensity (2.0 msec, 20 Hz) electrical stimulation of cervical vagal afferents (VAS) was studied in rats lightly anesthetized with pentobarbital. Serotonin (methysergide, LY 53857 or ICS 205-930), adrenergic (prazosin or yohimbine) or opioid (naloxone, nor-binaltorphimine or naltrindole) receptor antagonists were administered into the subarachnoid space of the lumbar enlargement to characterize the spinal receptors mediating VAS-produced facilitation. Spinal 5-HT1 and kappa-opioid receptors were determined to be involved in facilitation of the TF reflex produced by VAS, suggesting that facilitation of spinal nociceptive transmission by activation of cervical vagal afferents is mediated by subtypes of spinal serotonergic and opioid receptors.

Electrical stimulation in the nucleus reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) produces facilitation and/or inhibition of spinal nociceptive transmission in behavioral and electrophysiological studies. The present study examined spinal neurotransmitter receptors mediating descending facilitation from the NGC/NGC alpha. As previously demonstrated, electrical stimulation in the NGC/NGC alpha at low intensities (approximately equal to 10 microA) produced facilitation and at greater intensities (approximately equal to 38 microA) inhibition of the tail-flick (TF) reflex. Intrathecal pretreatment with the non-selective serotonin (5-HT) receptor antagonist methysergide attenuated or completely abolished facilitation of the TF reflex produced by electrical stimulation in the NGC/NGC alpha; intrathecal pretreatment with atropine, phentolamine, naloxone or mecamylamine was without effect on stimulation-produced facilitation. Descending inhibition from the NGC/NGC alpha produced by electrical stimulation was attenuated or completely abolished by bilateral transection of the dorsolateral funiculi (DLF) of the cervical spinal cord. Descending facilitation produced by electrical stimulation, however, was unaffected or enhanced following DLF transections. Glutamate microinjections (1.7 nmol/0.17 microliters) into the NGC/NGC alpha produced a rapid, repeatable and short-duration facilitation of the TF reflex in rats with bilateral DLF transections and such facilitation was attenuated by intrathecal pretreatment with methysergide, but not atropine, xylamidine (5-HT2 selective receptor antagonist) or MDL-72222 (5-HT3 selective receptor antagonist). These findings suggest that facilitation of the TF reflex from the activation of the cell bodies in the NGC/NGC alpha is mediated by a descending serotonergic pathway traveling in the ventrolateral funiculi and by spinal 5-HT1 receptors.

Deep pain arising from muscle, joints, connective tissue, and the viscera is different in character and quality from pain arising from cutaneous structures. Deep pains, particularly visceral pain, are poorly localized, typically referred or transferred to a cutaneous site, and generally produce strong emotional and autonomic responses and tonic muscle contractions. Despite the prevalence and clinical importance of deep pains, it is only relatively recently that investigative efforts have begun to focus on the mechanisms of deep pain. The present report briefly reviews the development and use of a model of visceral pain that employs constant pressure distension of the colon and rectum as a noxious stimulus. Converging behavioral, pharmacological, and physiological evidence that colorectal distension is a valid, reliable, noxious, visceral stimulus is presented.

The present study examined the role of the A5 catecholamine-containing cell group in descending modulation of the nociceptive tail-flick (TF) reflex and regulation of blood pressure and heart rate in rats lightly anesthetized with pentobarbital. Systematic mapping studies throughout the A5 cell group, rostral to caudal, showed that electrical stimulation in and near the A5 cell group at intensities as low as 25 microA was sufficient to inhibit the tail-flick (TF) reflex without producing a significant pressor response. Microinjections of glutamate into the same sites to selectively activate cell bodies also produced inhibition of the TF reflex and were accompanied by significant decreases in blood pressure (mean, -23 +/- 4.7 mmHg, n = 21) and non-significant decreases in heart rate (-7.6 +/- 11 bpm). Intrathecal administration of the receptor antagonists phentolamine, yohimbine, prazosin, methysergide, naloxone or atropine revealed that descending inhibition from the A5 cell group produced by electrical stimulation is mediated in part by spinal opioid and alpha-adrenoceptors. Increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex of 28.3 and 24.1% were produced by intrathecal pretreatment with phentolamine and naloxone, respectively. None of the other receptor antagonists produced significant increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex. Resting blood pressure and heart rate were not affected by the receptor antagonists.

The mechanisms of the antinociceptive, depressor and bradycardic responses produced by intravenous (i.v.) administration of morphine were examined in rats lightly anesthetized with pentobarbital sodium. Intravenous administration of 0.1, 0.25, 0.5, 1.0 or 2.5 mg/kg of morphine produced dose-dependent inhibition of the nociceptive tail flick (TF) reflex, hypotension, and bradycardia. Bilateral cervical vagotomy (CVAG) significantly attenuated the antinociception produced by i.v. morphine and the degree of attenuation was inversely related to drug dose. CVAG had no effect on the depressor response produced by lesser doses of morphine (0.1 or 0.5 mg/kg), but at greater doses converted the depressor response into either a pressor response (1.0 mg/kg) or an initial pressor response followed by a depressor response (2.5 mg/kg). Morphine-induced bradycardia was blocked by CVAG at all drug doses tested (0.1, 0.5, 1.0 and 2.5 mg/kg). In selective tests of either 0.5 or 2.5 mg/kg of i.v. morphine, prior administration of the peripherally acting opioid receptor antagonist naloxone methobromide (NMB) attenuated the antinociception to the same degree as CVAG. NMB also completely blocked the depressor and bradycardic responses of these doses of morphine. Bilateral subdiaphragmatic vagotomy (SDVAG) resulted in a marginal attenuation of antinociception at 0.5 mg/kg but not 2.5 mg/kg of morphine, and the attenuation produced by SDVAG was delayed in onset following morphine administration relative to that produced by CVAG. Bilateral sino-aortic deafferentation (SAD) had no significant effect on the antinociception in tests with 0.5 mg/kg of morphine. SDVAG and SAD had little effect on cardiovascular responses produced by these doses of morphine. The spinal antinociceptive systems activated by vagal afferents following i.v. morphine administration were characterized with the 0.5 mg/kg dose. Spinal cold block significantly antagonized the antinociception, hypotension and bradycardia produced by this dose of morphine. Intrathecal administration of naloxone (1.5, 15 or 30 micrograms) significantly antagonized the antinociception compared to saline controls, whereas intrathecal administration of methysergide (30 micrograms), phentolamine (30 micrograms), or the combination of methysergide with phentolamine (30 micrograms each) had no significant effect on the antinociception. These intrathecal doses of naloxone also antagonized the depressor and bradycardic responses produced by morphine. However, the antagonism produced by 1.5 micrograms of intrathecal naloxone was not due to spread to the systemic circulation, since i.v. administration of 1.5 micrograms of naloxone did not significantly affect either the antinociceptive or cardiovascular responses produced by morphine. These findings indicate that vagal afferents play a significant role in the antinociception produced by i.v. administration of morphine.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of electrical stimulation of cervical vagal afferents (VAS) on the background activity and on the responses of 25 spinothalamic tract (STT) neurons to noxious stimuli were studied in anesthetized rats. Background (spontaneous) activity of 9 (36%) STT neurons was inhibited by all intensities of VAS. 6 (24%) units were facilitated at lesser and inhibited at greater intensities of VAS, 5 (20%) units were only facilitated by all intensities of VAS, and 5 (20%) units were not affected by VAS. Responses of 8 (36%) STT neurons to noxious stimuli were only inhibited by VAS, 9 (41%) were facilitated at lesser and inhibited at greater intensities of VAS, and 5 units (23%) were only facilitated by VAS. There were no significant differences in VAS-produced modulatory effects between STT neurons and 16 unidentified lumbar spinal dorsal horn neurons studied under the same conditions. These results reveal that descending facilitatory and inhibitory pathways engaged by activation of vagal afferents modulate rostrally projecting nociceptive transmission neurons in the spinal cord, constituting an important regulatory network for nociception.

The intravenous (i.v.) administration of serotonin (5-HT) to lightly pentobarbital-anesthetized rats is known to produce a triad of reflex cardiovascular responses, distinct afferent-mediated pseudaffective reactions, and a vagally mediated inhibition of the nociceptive tail-flick (TF) reflex consistent with 5-HT acting as a noxious stimulus. In the present experiments we examined the involvement of capsaicin-sensitive afferents in mediating these responses. Lightly pentobarbital-anesthetized 16-week-old male Sprague-Dawley rats which had been treated as neonates (in the first 48 h of life) with capsaicin (50 micrograms/kg, s.c.) were compared to age-matched neonatal vehicle-treated controls. Whereas the i.v. administration of 5-HT produced a dose-dependent (6-96 micrograms/kg, i.v.) inhibition of the nociceptive TF reflex (ED50 = 48.1 +/- 11.3 micrograms/kg; n = 7) and distinct pseudaffective responses (usually by 24-48 micrograms/kg) in vehicle-treated rats, 5-HT (6-192 micrograms/kg, i.v.) failed to significantly alter TF latency or produce pseudaffective behaviors in the capsaicin-treated rats (n = 10). There was no difference in baseline TF latencies between the two groups. There were essentially no differences between vehicle- and capsaicin-treated rats with respect to the initial cardiopulmonary vagal afferent-mediated (Bezold-Jarisch reflex) decreases in heart rate and arterial blood pressure or the subsequent pressor phase. However, the magnitude of the late hypotensive phase was significantly greater in capsaicin-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have identified a site in lateral hypothalamus (LH) in which electrical stimulation elicits coronary vasoconstriction. We injected the retrogradely transported tracer Fast Blue to determine which brain regions project to LH. Projections to or through LH were found from the paraventricular nucleus (PVN) of the hypothalamus, bed nucleus of the stria terminalis (BNST), and dorsal raphe nucleus (DRN). In chloralose-anesthetized cats, electrical stimulation in DRN and BNST failed to increase coronary vascular resistance (CVR). However, stimulation lateral to PVN in the anterior hypothalamic area (AHA), a region not labeled by the tracer, caused a transient decrease in coronary blood flow similar to that elicited from LH. The increase in CVR was accompanied by hemodynamic changes that are characteristic of the defense reaction including a cholinergically mediated decrease in hindquarter vascular resistance. This response is likely due to activation of fibers of passage and not cell bodies, since cell bodies in the region were not retrogradely labeled and coronary vasoconstriction was not seen following microinjection of several excitatory amino acids into AHA. These data suggest that coronary vasoconstriction may be a component of the defense reaction elicited by electrical activation of AHA.

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.

This study compared the cutaneous (baseline tail-flick (TF) latencies) and visceral nociceptive responses (5-HT-induced inhibition of the TF reflex and pseudaffective responses) in lightly pentobarbital-anesthetized 16 week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). SHR were significantly less sensitive to the nociceptive effect of i.v. 5-HT compared to WKY rats. That is, SHR had a greater quantal ED50 for inhibition of the TF reflex than WKY rats (50.0 and 15.1 micrograms/kg, respectively). SHR also showed the presence of distinct pseudaffective responses (flattening of the ears, closure of the eyes to slits and contraction of the facial musculature) at much greater doses than in WKY rats, thereby paralleling the same changes in sensitivity observed the 5-HT-induced inhibition of the TF reflex. 5-HT-induced similar cardiovascular responses in WKY and SHR except that the SHR showed a significantly greater pressor response compared to WKY rats. These results demonstrate that the SHR show a marked reduction in sensitivity to the nociceptive, but not the cardiovascular, responses to i.v. 5-HT.

Focal electrical stimulation and glutamate microinjection in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) both inhibit the nociceptive tail-flick (TF) reflex in rats. The present experiments were undertaken to determine the transmitter(s) at the level of the lumbar spinal cord mediating descending inhibition of the TF reflex produced by activation of the NGC/NGC alpha. Intrathecal administration of atropine (7.2-57.6 nmol) produced a dose-dependent increase in the electrical stimulation threshold required for inhibition of the TF reflex. Phentolamine (47.2 or 94.4 nmol) and methysergide (32 or 64 nmol) also increased the stimulation threshold significantly, but only at the greater doses. Neither naloxone (27.5 or 55 nmol) nor mecamylamine (49.1 or 98.2 nmol) affected stimulation thresholds for inhibition of the TF reflex. Stimulation at threshold intensities for inhibition did not change the blood pressure significantly at most sites of stimulation in the NGC/NGC alpha (25/39). Intrathecal administration of atropine, phentolamine or methysergide did not affect resting blood pressure or changes associated with stimulation in most cases, although inhibition of the TF reflex by stimulation in the NGC/NGC alpha was affected consistently by these pretreatments. Similarly, glutamate (100 nmol, 0.5 microliter/1.5 min) microinjection produced a short-lasting inhibition (4.63 +/- 0.70 min, n = 19) of the TF reflex. Glutamate microinjection produced both pressor and depressor effects which were not affected by intrathecal pretreatment. Inhibition of the TF reflex by glutamate was attenuated significantly by intrathecal pretreatment with atropine, scopolamine, phentolamine and methysergide, but not naloxone or mecamylamine. These findings suggest that either a descending or local spinal cholinergic system, together with descending serotonergic and noradrenergic systems, are involved in the centrifugal inhibition of spinal nociceptive transmission from the NGC/NGC alpha.

Psychophysiological experiments were performed in 9 humans using constant-pressure, phasic, graded distention (30 sec, 20-70 mm Hg) of the sigmoid colon as a visceral stimulus. Reliable cardiovascular (pressor), respiratory and visceromotor responses in addition to reports of pressure/pain sensations were evoked by colonic distension in 8 of the 9 subjects. The pressure/pain sensations were referred to the lower abdomen, lower back and perineum and their intensity quantified using a visual analogue scale. Responses to colonic distension were graded and increased with repeated distensions at the same intensity (60 mm Hg). The area of referral as indicated by subject drawings increased with repeated distensions as did the intensity of the subjects' sensory and affective descriptors of the sensation. Five of the subjects differentiated between 'pressure' and 'pain' sensations evoked by colonic distension; the intensity of the 'pain' sensation accelerated during the distending stimulus whereas the 'pressure' sensation was typically stable or adapting during the distending stimulus.

Many of the circulating algesic agents released in response to ischemia produce a profound vasodilatation possibly through the release of an endothelium-derived relaxing factor (EDRF) as well as pain. We report here that intravenously administered S-nitrosocysteine, a putative EDRF, and not the nitric oxide liberating compound sodium nitroprusside produces significant alterations in nociceptive behavior that are abolished by bilateral vagotomy. These results are consistent with a role for EDRF in peripheral nociceptive mechanisms.

1. Supraspinal relays for vagal afferent modulation of responses of spinal dorsal horn neurons to 50 degrees C heating of the skin were examined by the use of nonselective, reversible local anesthesia or soma-selective, irreversible neurotoxic damage of neural tissue. Eighty-five neurons were isolated in the lumbar spinal dorsal horn of 80 pentobarbital-anesthetized, paralyzed rats. All neurons studied had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind paw and responded to mechanical stimuli of both low and high intensity as well as noxious thermal stimulation. 2. Intensity-dependent modulation by vagal afferent stimulation (VAS) of neuronal responses to heating of the skin was established. Responses of 40 units were facilitated by low and inhibited by greater intensities of VAS. Another 36 units were only inhibited by VAS, and four were only facilitated. 3. Local anesthesia of the dorsolateral pons by bilateral microinjections of lidocaine (4%, 0.5 microliter) were made to examine the contribution of this area to VAS-produced spinal modulation. The microinjection of lidocaine bilaterally into the ventral locus coeruleus/subcoeruleus (LC/SC) reversibly and significantly attenuated VAS-produced inhibition of unit responses to heat from 63 to 89% of control and abolished VAS-produced facilitation. The microinjection of lidocaine bilaterally into the dorsal LC had no significant effect on VAS-produced modulation of spinal dorsal horn neurons. 4. Ibotenic acid (10 micrograms, 0.5 microliter) was microinjected into the dorsolateral pons to determine the relative contributions of cell bodies in this area to VAS-produced spinal modulation. Unilateral microinjection of ibotenic acid into the LC/SC ipsilateral to the vagus nerve stimulated had no significant effect on VAS-produced inhibition but significantly attenuated VAS-produced facilitation of unit responses to heat. Bilateral microinjections of ibotenic acid significantly attenuated VAS-produced inhibition of unit responses to heat from 48 to 94% of control. 5. Local anesthesia of the medial rostroventral medulla (RVM), primarily the nucleus raphe magnus (NRM), significantly attenuated VAS-produced inhibition of unit responses to heat from 55 to 87% of control but had no significant effect on VAS-produced facilitation. Microinjection of ibotenic acid into the RVM also significantly reduced VAS-produced inhibition of unit responses to heat. No significant change in VAS-produced spinal modulation was found after lidocaine microinjection into areas dorsal to the NRM, the nucleus raphe pallidus, or the olivary nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Supraspinal substrates mediating vagal afferent stimulation (VAS)-induced inhibition of the nociceptive tail-flick reflex were examined by the use of the soma-selective neurotoxin ibotenic acid and the nonselective local anesthetic lidocaine. Fifty rats were studied in the lightly anesthetized state maintained with pentobarbital sodium. 2. The threshold intensity of VAS required to inhibit the tail-flick reflex to a cut-off latency of 10 s was established in all rats. Ibotenic acid (5 or 10 micrograms, 0.5 microliter) or lidocaine (4%, 0.5 microliter) was then microinjected into various regions of the brain stem followed by reestablishment of the intensity of VAS required to produce inhibition of the tail-flick reflex. 3. Microinjections of ibotenic acid into the ipsilateral nucleus tractus solitarius (NTS), medial rostroventral medulla (principally the nucleus raphe magnus; NRM), or bilaterally into the dorsolateral pons (principally the locus coeruleus/subcoeruleus; LC/SC), significantly increased the threshold intensity of VAS required to inhibit the tail-flick reflex. Microinjections of ibotenic acid into either the rostral or caudal ventrolateral medulla (RVLM or CVLM, respectively) ipsilateral to the vagus nerve stimulated or ipsilateral LC/SC did not significantly affect the inhibition produced by VAS. Arterial blood pressure decreases produced by VAS were significantly attenuated or eliminated after microinjections of ibotenic acid into the NTS, RVLM, CVLM, or NRM. Lidocaine microinjected into the ipsilateral CVLM also significantly increased the intensity of VAS required to inhibit the tail-flick reflex. 4. These outcomes obtained with behavioral measures are consistent with the outcomes of the preceding study using electrophysiological measures in establishing that cells in the NTS, LC/SC, and NRM regions and fibers of passage in the CVLM are important in mediating the inhibitory effects of VAS. The present studies confirm previous reports of the importance of the RVLM and CVLM in VAS-produced depressor responses but also demonstrate that the NRM is critical for this cardiovascular response.

We have recently identified discrete sites within the lateral hypothalamus and medullary reticular formation that, when stimulated electrically, produce neurally mediated coronary vasoconstriction. This study examined whether these sites are part of the same coronary vasomotor pathway. The neuronal tracing dye fast blue was injected in cats into the coronary vasoconstrictor site within medullary reticular formation. Fluorescence microscopy revealed major afferent projections originating from within the same region of midbrain ventrolateral periaqueductal gray that receives projections from lateral hypothalamus. To determine the functional importance of the proposed connections between the hypothalamic and medullary sites, anesthetized cats were prepared for continuous hemodynamic measurements. Constant current electrical stimulation within lateral hypothalamus produced significant increases in heart rate (21 +/- 6%), arterial pressure (11 +/- 3%), and femoral (36 +/- 18%) and coronary resistances (14 +/- 9%) with no change in coronary flow velocity (-1.1 +/- 2.5%). After beta-adrenoreceptor blockade, significantly greater increases in arterial pressure (35 +/- 8%) and coronary resistance (39 +/- 5%) with transient decreases in coronary flow velocity (21 +/- 6%) were seen. Microinjections of lidocaine into the medullary site blocked coronary constriction produced by lateral hypothalamic stimulation (39 +/- 5% increase in coronary resistance to electrical stimulation before and 2.4 +/- 2% increase after lidocaine in medullary reticular formation). These data provide evidence that specific regions of lateral hypothalamus and medullary reticular formation are part of a common central vasomotor projection that mediates coronary vasoconstriction in addition to other hemodynamic effects.

Descending influences on the spinal nociceptive tail-flick (TF) reflex produced by focal electrical stimulation and glutamate microinjection in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) were examined and characterized in rats lightly anesthetized with pentobarbital. Both inhibition and facilitation of the TF reflex were produced by electrical stimulation at identical sites in the NGC/NGC alpha; glutamate microinjection only inhibited the TF reflex. The chronaxie of stimulation for inhibition of the TF reflex was 169 +/- 28 microseconds. Inhibition of the TF reflex by stimulation was produced throughout the NGC and NGC alpha; intensities of stimulation for inhibition were least in the ventral NGC and in the NGC alpha. At threshold intensities of stimulation, inhibition of the TF reflex did not outlast the period of stimulation. Facilitation of the TF reflex was produced at many of the same sites at which stimulation inhibited the TF reflex, but always at lesser intensities of stimulation (mean, 10 microA vs. 43 microA for inhibition, n = 25). Stimulation in the NGC/NGC alpha at threshold intensities for facilitation or inhibition of the TF reflex did not significantly affect blood pressure. Strength-duration characterization of electrical stimulation and microinjection of glutamate into identical sites in the NGC and NGC alpha suggest that descending inhibition of the TF reflex results from activation of cell bodies in the NGC and NGC alpha.

The effect of intravenous (i.v.) serotonin (5-HT) on nociception and blood pressure was examined in male Sprague-Dawley rats. Intravenous 5-HT produced a dose-dependent (6-192 micrograms/kg, i.v.) inhibition of the nociceptive tail-flick (TF) reflex in lightly pentobarbital-anesthetized (ED50 = 40 micrograms/kg) and conscious rats (ED50 = 44 micrograms/kg). In the lightly pentobarbital-anesthetized rat, the blood pressure response to i.v. 5-HT was typically a triphasic response with a marked Bezold-Jarisch reflex-induced decrease in pressure (associated with a brief period of apnea) followed by a pressor phase and a subsequent delayed hypotension. In the conscious rat, the response was typically biphasic with the late hypotensive phase absent. A variety of anatomical and pharmacological manipulations were performed to characterize the 5-HT-induced inhibition of the TF reflex and associated changes in blood pressure. Prevention of 5-HT-induced reflex apnea by artificial ventilation did not affect inhibition of the TF reflex produced by 5-HT. Pharmacological manipulations were performed to mimic, as closely as possible, the acute increases and decreases in blood pressure associated with i.v. 5-HT. Nitroprusside (8 micrograms/kg, i.v.) produced a decrease in blood pressure of similar magnitude and rate as that associated with the Bezold-Jarisch reflex-induced decrease in pressure produced by 72 micrograms/kg 5-HT, but did not change TF latency from baseline. Similarly, acute increases in pressure produced by phenylephrine (8 micrograms/kg, i.v.), intended to mimic the secondary pressor effect of 5-HT, did not change TF latency. The short-acting ganglion blocker trimethaphan (5 mg/kg, i.v.) closely mimicked the late hypotensive phase produced by 5-HT, but again resulted in no change in TF latency. Pretreatment with the ganglion blocker chlorisondamine (2.5 mg/kg) abolished all depressor responses to 72 micrograms/kg 5-HT, but did not significantly affect the TF reflex. These results indicate that acute changes in blood pressure and respiration associated with i.v. 5-HT do not contribute to inhibition of the TF reflex. This conclusion was confirmed in experiments in which bilateral vagotomy abolished approximately 70% of the 5-HT-induced inhibition of the TF reflex (and all depressor responses), and resulted in a significantly greater pressor response. Finally, low thoracic spinal cord transection (T9-10) abolished the inhibition of the TF reflex produced by i.v. 5-HT. Therefore, 5-HT stimulates vagal afferents and inhibits the TF reflex by activating descending inhibitory systems from the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)

To test the hypothesis that baroreceptor reflexes are involved in the reduced nociceptive responses associated with hypertension, the effects of acute intravenous doses of serotonin (0.75-144 micrograms/kg) on inhibition of the tail-flick reflex, blood pressure, and heart rate were examined in lightly pentobarbital-anesthetized Sprague-Dawley, Wistar-Kyoto, and spontaneously hypertensive rats before and after bilateral transection of the aortic depressor nerve. Before transection, the ED50s for inhibition of the tail-flick reflex in the three strains of rats were 14, 13, and 44 micrograms/kg, respectively. After bilateral transection of the aortic depressor nerve, all three strains displayed a significant increase in sensitivity toward the serotonin-induced inhibition of the tail-flick reflex (ED50s of 7, 7, and 6 micrograms/kg, respectively). There were no changes in the cardiovascular responses to serotonin after transection of the aortic depressor nerve in Wistar-Kyoto or spontaneously hypertensive rats. In Sprague-Dawley rats, however, the cardio-pulmonary cardiovascular afferent-mediated responses were enhanced. In Sprague-Dawley rats, the nociceptive sensitivity to serotonin was unaltered when administered during either the peak increase or decrease in pressure produced by intravenous phenylephrine or nitroprusside, respectively. These results suggest that 1) afferent fibers within the aortic depressor nerve provide strong tonic inhibitory influences on the noxious information conveyed by the vagus in response to intravenous serotonin and 2) these fibers appear to produce their effects by mechanisms that are unrelated to baroreceptor function.

Intrathecal administration of alpha adrenoceptor agonists in rats produces a significant elevation of nociceptive thresholds as measured by hot-plate and tail-flick latencies. That these antinociceptive effects were antagonized by alpha adrenoceptor antagonists suggests that spinal adrenoceptors modulate the rostrad transmission of nociceptive information. The role of spinal adrenoceptors in the modulation of nociception in visceral pain tests has in the past been examined primarily in the writhing model of visceral pain. Recently, however, a new model of visceral pain has been developed which utilizes colorectal distension (CRD) as the noxious visceral stimulus in awake, unanesthetized animals. CRD produces a pressor response and contraction of the abdominal and hindlimb musculature (a visceromotor response), both of which are readily quantifiable. Inhibition of both of these pseudoaffective reflexes is indicative of antinociception. The effects of intrathecally administered adrenoceptor agonists on the responses to CRD were examined in conscious rats. The visceromotor and pressor responses to CRD were dose-dependently inhibited by the alpha-2 adrenoceptor agonists clonidine and ST-91 and the nonselective alpha adrenoceptor agonist norepinephrine (NE), but not by the alpha-1 adrenoceptor agonist methoxamine or the alpha adrenoceptor agonist isoproterenol. Tizanidine, an alpha-2 adrenoceptor agonist, dose-dependently inhibited the pressor response to CRD but failed to significantly elevate the visceromotor threshold in response to CRD. The effects produced by clonidine, NE and ST-91 were antagonized by pretreatment with yohimbine. The effects produced by tizanidine were antagonized by idazoxan.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper reviews clinical and basic science research reports and is directed toward an understanding of visceral pain, with emphasis on studies related to spinal processing. Four main types of visceral stimuli have been employed in experimental studies of visceral nociception: (1) electrical, (2) mechanical, (3) ischemic, and (4) chemical. Studies of visceral pain are discussed in relation to the use and 'adequacy' of these stimuli and the responses produced (e.g., behavioral, pseudoaffective, neuronal, etc.). We propose a definition of an adequate noxious visceral stimulus and speculate on spinal mechanisms of visceral pain.

1. The effects of electrical and chemical stimulation in the nucleus tractus solitarii (NTS) on spinal nociceptive transmission were examined in pentobarbital sodium-anesthetized, paralyzed rats. These studies also examined the role of the NTS as a relay for the effects of vagal afferent stimulation (VAS) on spinal nociceptive transmission. All 75 neurons studied were located in laminae I-VI in the L3-L5 spinal segments, with receptive fields on the glabrous skin of the plantar surface of the ipsilateral hindpaw. The units responded to mechanical (low and/or high intensities) and thermal stimuli (42-52 degrees C). 2. Electrical stimulation in the NTS either ipsilateral or contralateral to the spinal unit inhibited neuronal responses to noxious thermal stimuli. The magnitude of inhibition did not significantly differ as a function of either ipsilateral (15 units) or contralateral (12 units) NTS stimulation (NTSS) as indicated by extrapolated thresholds for inhibition of responses to heat, intensities to produce 50% inhibition of responses to heat, and the slope of recruitment lines for inhibition. Tracking experiments also revealed that stimulation in the area ventral to the NTS produced a greater magnitude of inhibition of these units than did NTSS. 3. NTSS significantly decreased the slope of the stimulus-response functions (SRFs) of dorsal horn units to graded thermal stimuli (42-52 degrees C), whereas response threshold was unaffected by NTSS. The apparent latency of NTSS to produce inhibition of unit responses to heating of the hindpaw was determined to be 50 +/- 10 ms (mean +/- SE). 4. Microinjection of 50 nmol of glutamate into the NTS ipsilateral to the spinal unit also inhibited neuronal responses to thermal stimuli in 17/21 units; responses of 2/21 units were facilitated. Inhibition typically lasted 4-7 min and was shown to be dose-volume dependent. 5. The effects of VAS and NTSS on spinal nociceptive transmission were directly compared. The responses of 17 units to 50 degrees C heating of the hindpaw were facilitated by low and inhibited by greater intensities of VAS (Biphasic units); the responses of 12 units were only inhibited by VAS (Inhib units); three were only facilitated (Facil units), and 2 were unaffected by VAS. In contrast, NTSS generally inhibited the same spinal units, although modest facilitation was produced by NTSS contralateral to the recording site. NTSS produced greater inhibition of the Biphasic units than did VAS, shown by a leftward shift of the recruitment line of inhibition and greater inhibition at the same intensity of electrical stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Several lines of evidence implicate bulbospinal noradrenergic pathways in antinociception and descending inhibition. In the present study, descending inhibition of the nociceptive tail-flick (TF) reflex by electrical stimulation in the dorsolateral pons (DLP) and the spinal neurotransmitter(s) mediating that inhibition were characterized in lightly pentobarbital-anesthetized rats. It was determined that 10 s of stimulation in the DLP prior to the application of heat to the tail resulted in optimum (lowest) thresholds for inhibition of the TF reflex. Conditioning-test studies indicated that the duration of the inhibitory effects produced by stimulation outlasted the 10-s period of stimulation by approximately 5 s. Systematic mapping studies revealed that inhibition of the TF reflex could be produced by stimulation throughout a large portion of the DLP; however, stimulation sites requiring the lowest intensities of stimulation (less than or equal to 25 microA) were in the locus coeruleus/subcoeruleus. Changes in blood pressure were not produced at this intensity and duration of stimulation. S-glutamate microinjections and stimulation strength-duration determinations suggest that inhibition of the TF reflex produced by stimulation in the locus coeruleus/subcoeruleus results from activation of cell bodies. The intrathecal administration of pharmacologic antagonists (phentolamine, yohimbine, prazosin, naloxone, methysergide, atropine and bicuculline) revealed that only the alpha-adrenergic antagonists phentolamine and yohimbine resulted in significant increases in stimulation thresholds in the locus coeruleus/subcoeruleus for inhibition of the TF reflex (83.1 and 93.9%, respectively). These results indicate that inhibition of the spinal nociceptive TF reflex produced by electrical stimulation in the locus coeruleus/subcoeruleus is at least in part a noradrenergic, postsynaptic alpha 2-adrenoceptor-mediated effect.

The organization in the brainstem of descending pathways of spinal inhibition was examined in the lightly pentobarbital-anesthetized rat. Thresholds for focal electrical stimulation-produced inhibition of the spinal nociceptive tail flick (TF) reflex were determined at one stimulation site in the midbrain periaqueductal gray and three sites in the rostral medulla: nucleus raphe magnus, and the adjacent medullary reticular formation contralateral and ipsilateral to the stimulating electrode in the periaqueductal gray. Lidocaine (0.5 microliter, 4%) was subsequently microinjected in the same and other medullary loci in the same coronal plane to produce a time-limited, reversible functional neural block. The functional block produced by 0.5 microliter of lidocaine microinjected in the medulla was determined to have a radius of 0.5 mm and was maximally efficacious during the first 30 min after its intramedullary microinjection. The stimulation threshold in the periaqueductal gray for inhibition of the TF reflex was not increased significantly when either the nucleus raphe magnus was fully blocked by lidocaine microinjected in three dorsoventral positions 1.0 mm apart or when the medullary reticular formation ipsilateral and contralateral were simultaneously fully blocked. Not until the nucleus raphe magnus and medullary reticular formation ipsilateral were simultaneously blocked by lidocaine was the stimulation threshold in the periaqueductal gray for inhibition of the TF reflex significantly increased. An increase in the periaqueductal gray stimulation threshold twice as great resulted when the nucleus raphe magnus and both the ipsilateral and contralateral medullary reticular formations were all simultaneously blocked by lidocaine. These results indicate that: (1) the nucleus raphe magnus is not a necessary bulbar relay in a descending antinociceptive pathway activated by stimulation in the midbrain periaqueductal gray; and (2) descending inhibitory pathways activated in the periaqueductal gray course medially as well as laterally in the rat ventral medulla.

The nucleus locus coeruleus (LC) has been implicated in the descending inhibition of spinal nociceptive dorsal horn neurons, spinal nociceptive reflexes and in the antinociception produced by morphine. To further explore the involvement of the LC in antinociception, bilateral electrolytic lesions in the LC were made in adult male Sprague-Dawley rats. Lesions in the LC did not alter the antinociception produced by morphine (2.5 and 5 micrograms) administered in the periaqueductal gray in either the tail-flick (TF) or hot-plate (HP) tests when tested 7 and 14 days after the lesions. Baseline nociceptive thresholds in the TF and HP tests likewise were not affected at 7 or 14 days post-lesion. In contrast, the antinociceptive potency of clonidine administered intrathecally on day 13 post-lesion was enhanced significantly in the TF test; the antinociceptive ED50 of the LC lesion group was 0.52 micrograms whereas that of the sham lesion group was 2.29 micrograms. The antinociceptive potency of clonidine administered systemically (750 and 500 micrograms/kg, s.c.) was also enhanced in the LC lesion group in the TF but not the HP test. Norepinephrine (NE) in the lumbar spinal cord was correlated negatively and significantly with the extent of destruction of the LC. The lumbar spinal content of NE was reduced maximally at 12 days post-lesion (to 56% of control). The binding of [3H]clonidine in the lumbar spinal cord was slightly greater in the LC lesion than sham lesion group; the Bmax values were 42.4 fmol/mg protein and 35.5 fmol/mg protein for the LC lesion and sham lesion groups, respectively. It is suggested that the LC participates in the descending inhibition of spinal nociceptive transmission and that this inhibition may be mediated in the spinal cord by alpha-2 adrenoceptors located postsynaptically with respect to the NE terminals of the spinopetal LC efferents.

Infant and adult rats were injected chronically with either naloxone or saline for 21 consecutive days. At various intervals after cessation of the pretreatment with naloxone, animals were sacrificed and assessed for specific binding of [3H]naloxone in different regions of the CNS. Infants displayed an increase in opiate binding in the spinal cord, hypothalamus, striatum and cortex one day after cessation of the pretreatment with naloxone, but the increase in opiate binding was dissipated within one week after cessation of the pretreatment. The increase in opiate binding in infants was accompanied by an increase in the antinociceptive efficacy of morphine. In contrast to infants, adults failed to display any alteration in opiate binding following the chronic pretreatment with naloxone. Infants may be especially susceptible to naloxone-induced receptor supersensitivity because infants excrete naloxone more slowly than adults, and thus their opiate receptors may be blocked for a longer duration following an injection of naloxone.

Several lines of evidence have demonstrated a role for the lateral hypothalamus (LH) in an endogenous system of descending inhibition. The present study, in rats lightly anesthetized with pentobarbital, was undertaken to examine systematically the organization in the brain stem of pathways mediating descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH. The microinjection of lidocaine into the midbrain, dorsolateral pons, or medial medulla resulted in significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (89.1, 67.4, and 73.6%, respectively). Selective lesions of cell bodies in the midbrain or medulla by the neurotoxin ibotenic acid also produced significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (31.6 and 131.6%, respectively), thus revealing relays in the periaqueductal gray and the nucleus raphe magnus located between the LH and the lumbar spinal cord. The failure of ibotenic acid to affect LH-produced descending inhibition when microinjected into the dorsolateral pons, and the significant effect produced by lidocaine microinjected into the same area, implicates fibers of passage in the dorsolateral pons in descending inhibition of the TF reflex produced by focal electrical stimulation in the LH. The fluorescent dye Fast blue and HRP conjugated to wheat germ agglutinin were used to confirm that the area stimulated in the LH has reciprocal connections with the periaqueductal gray and nucleus raphe magnus.

The lateral reticular nucleus (LRN) and locus coeruleus-subcoeruleus (LC/SC), brainstem structures which overlap the A1 and A6 noradrenergic nuclei respectively, have been implicated in descending modulation of spinal nociceptive transmission. The present studies were designed to examine the role of norepinephrine (NE) in the mediation of inhibition of the nociceptive tail flick reflex produced by focal electrical stimulation in the LRN and LC/SC. Spinal NE was depleted by intrathecal administration of 6-hydroxydopamine (6-OHDA; 20 micrograms) and the threshold electrical stimulation in the LRN and the LC/SC necessary to inhibit the tail flick reflex in lightly pentobarbital-anesthetized rats was determined 9 and 14 days later. Despite a significant depletion (greater than 85%) of lumbar spinal cord NE content, there was no significant change in the tail flick inhibitory stimulation thresholds in the LRN or LC/SC. NE depletion did, however, potentiate the elevation in the inhibitory stimulation threshold in the LRN produced by intrathecal administration of the alpha 2-adrenoceptor antagonist, yohimbine, suggesting that upregulation of spinal adrenoceptors had occurred following 6-OHDA treatment. Adrenoceptor up-regulation was examined quantitatively by characterizing the dose-dependent antinociceptive potency of the selective alpha 2-adrenoceptor agonist clonidine 3, 7, 10, and 14 days following 6-OHDA administration, and analysis of [3H]rauwolscine binding to lumbar spinal cord 9 days following administration of the neurotoxin. The development of supersensitivity, defined as the leftward parallel shift of the dose-response curves for clonidine administered intrathecally, corresponded to the time course of NE depletion following 6-OHDA treatment on the days tested. Binding of [3H]rauwolscine to lumbar spinal cord revealed an elevation in the estimated Bmax without a change in the estimated Kd of the high affinity binding component 9 days following 6-OHDA administration. This study demonstrates that spinal adrenoceptor denervation supersensitivity develops rapidly following intrathecal administration of 6-OHDA and compensates for the selective destruction of spinal noradrenergic nerve terminals. Thus, the absence of effect of NE depletion on the tail flick inhibitory stimulation threshold in the LRN and the LC/SC does not argue against the hypothesis that spinopetal NE-containing neurons in these brainstem loci are involved in modulation of spinal nociceptive transmission.

Modulation of the spinal nociceptive tail flick (TF) reflex by electrical stimulation of subdiaphragmatic or cervical vagal afferent fibers was characterized in rats lightly anesthetized with pentobarbital. Cervical vagal afferent stimulation (VAS) inhibited the TF reflex in a pulse width-, frequency-, and intensity-dependent fashion. The optimum parameters for inhibition of the TF reflex were determined to be 2.0 ms pulse width, 20 Hz frequency with a threshold (T) current of 60 microA. Cervical VAS at 0.2-0.6 T facilitated the TF reflex. Cervical VAS at T typically produced a depressor arterial blood pressure response, but inhibition of the TF reflex by VAS was not due to changes in blood pressure. Subdiaphragmatic VAS also inhibited the TF reflex and generally produced a pressor effect, but did not facilitate the TF reflex at intensities of stimulation less than T as did cervical VAS. The parameters of cervical VAS required for inhibition of TF reflex suggest that excitation of high-threshold, unmyelinated fibers are important in VAS-induced descending inhibition. The intrathecal administration of pharmacologic receptor antagonists into the subarachnoid space of the lumbar enlargement indicated that the opioid receptor antagonist naloxone produced a dose-dependent antagonism of cervical VAS-produced inhibition of TF reflex, but single doses of either phentolamine or methysergide (30 micrograms each) failed to affect the inhibition by VAS. Combined intrathecal injection of both phentolamine and methysergide (30 micrograms each), however, significantly attenuated inhibition of the TF reflex by cervical VAS. These results suggest that cervical VAS engages a spinal opioid system and co-activates descending serotonergic and noradrenergic systems to modulate spinal nociceptive processing.

The antinociceptive efficacy of clonidine, St-91, tolazoline, phenylephrine or isoproterenol microinjected in the periaqueductal gray (PAG) in the rat was compared to that of morphine administered in the same site. Morphine (5 micrograms) was antinociceptive in all 3 analgesiometric tests employed (tail-flick, hot-plate and tail-shock vocalization). Clonidine (5-20 micrograms) did not significantly alter nociceptive thresholds, while St-91 (20 micrograms) produced a brief hyperalgesia in the tail-flick test. The alpha-2 antagonist tolazoline (20 micrograms) produced a brief antinociception in the tail-flick test. Phenylephrine and isoproterenol were without effect on nociceptive thresholds. It is suggested that the ventrolateral PAG, although a site of opiate-produced antinociception, is not involved in alpha-2-mediated antinociception.

Recent studies have demonstrated a hypoalgesia in hypertensive subjects. This study reports and evaluates factors responsible for the expression of the hypoalgesic behavior demonstrated by genetically hypertensive rats of the Okamoto-Aoki strain (SHR) as compared to normotensive age-matched Wistar-Kyoto rats (WKY). Analgesiometric assays were conducted by the hot plate method. SHR's hypoalgesic behavior was reversed by subcutaneously administered naloxone. The intravenous administration of naloxone did not alter arterial pressure or heart rate in either SHR or WKY. Subcutaneous administration of the peripherally acting ganglionic blocker hexamethonium bromide at a dose which lowered mean arterial blood pressure and thus decreased tonic baroreceptor stimulation, concomitantly reversed the SHR hypoalgesic behavior and induced a hyperalgesia in WKY. Denervation of the sino-aortic baroreceptors failed to alter the hypoalgesic behavior demonstrated by SHR. Denervation of the right vagal nerve trunk with associated cardiopulmonary baroreceptor afferents resulted in a reduction of the SHR hypoalgesic behavior and produced a hyperalgesic behavior in WKY as compared to age-matched sham operated controls over a 4 week period. These data suggest a possible physiological role for vagal afferent systems in the concomitant regulation of resting arterial blood pressure and responsiveness to aversive environmental stimuli. A discussion of the interaction between blood pressure and pain regulatory systems as potential substrates associated with the onset and maintenance of hypertension is provided.

Four experiments examined the role of the nucleus tractus solitarius (NTS) and subjacent nucleus reticularis ventralis (NRV) in the production of antinociception. Experiment 1 showed that microinjection of glutamate (50 nmol) into the caudal NTS resulted in inhibition of the tail-flick reflex, hypotension, and mild bradycardia, whereas microinjection of glutamate into the rostral NTS resulted only in hypotension and mild bradycardia. Microinjections of glutamate into the NRV resulted in inhibition of the tail-flick reflex, hypertension, and mild bradycardia. Experiment 2 demonstrated that the magnitude of the antinociceptive and cardiovascular responses resulting from glutamate microinjections into both the depressor and pressor regions were dose dependent. Experiment 3 showed that the antinociceptive effects resulting from microinjections of glutamate into either the depressor or pressor regions could not be antagonized by phentolamine (30 micrograms), methysergide (30 micrograms), or naloxone (30 micrograms) alone, but the combined intrathecal administration of phentolamine and methysergide (7.5, 15, or 30 micrograms of each) attenuated the antinociception resulting from microinjection of glutamate into either depressor or pressor regions in a dose-dependent fashion. Experiment 4 showed that systemic administration of hexamethonium blocked the pressor response produced by microinjection of glutamate into the NRV but did not reduce the antinociceptive effect of the microinjection. These findings are consistent with a role for the NTS and NRV in the production of antinociception.

The lateral reticular nucleus (LRN) has been identified as an area in the caudal medulla involved in the centrifugal modulation of spinal nociceptive transmission and withdrawal reflexes. The data presented in this report further support a role for the LRN in the modulation of nociceptive responses. It was confirmed in the present study that focal electrical stimulation in the LRN inhibits the nociceptive tail-flick (TF) reflex at low intensities of stimulation in lightly pentobarbital-anesthetized rats. Aversive effects, however, were typically produced at similar and higher intensities of stimulation in the LRN in the same rats in the awake state. It was also determined that an inhibitory modulation of nociceptive responses organized both spinally and supraspinally could be activated independently by muscarinic cholinergic or opioid mechanisms in the LRN. Microinjection of morphine into the LRN in conscious rats produced an antinociception in both TF and hot plate (HP) tests which could be attenuated significantly by naloxone, but not atropine, previously microinjected into the same site in the LRN. Carbachol microinjected into the LRN also produced an antinociception which was attenuated significantly by atropine but not naloxone previously microinjected into the same site in the LRN. In contrast, the microinjection of clonidine or norepinephrine into the LRN either did not affect or shortened significantly response latencies in the TF and HP tests. These results further establish that the LRN contributes to the modulation of nociception. Opioid and cholinergic influences in the LRN appear to independently activate inhibition of responding to nociceptive stimuli organized either spinally or supraspinally, although descending inhibition was most clearly activated. An action at alpha 2 adrenoceptors in the LRN, conversely, produces an hyperalgesia as reflected by shortened latencies to respond in TF and HP tests.

Inhibition of the spinal nociceptive tail-flick (TF) reflex by focal electrical stimulation in the caudal medulla was examined and characterized in lightly pentobarbital-anesthetized rats. Systematic mapping studies revealed that inhibition of the TF reflex was produced at low intensities of stimulation (12.5-25 microA) only from the lateral reticular nucleus (LRN). Areas dorsal and medial to the LRN required higher intensities of stimulation to produce descending inhibition of the TF reflex, likely reflecting spread of current to the LRN at these higher intensities of stimulation (50-100 microA). At threshold inhibitory intensities of stimulation in the LRN, changes in blood pressure were not produced. Strength-duration characterization of stimulation and the microinjection of glutamate into the LRN at the same site where focal electrical stimulation was effective suggest that the descending inhibition produced arises from activation of cell bodies in the LRN. The intrathecal administration of a variety of pharmacological antagonists revealed the descending inhibition produced by stimulation in the LRN to be mediated at least in part by spinal alpha 2-adrenoceptors. These findings, together with previous observations, suggest a role for the LRN in the centrifugal modulation of spinal nociceptive transmission.

Inhibition of the spinal nociceptive tail flick (TF) reflex by electrical stimulation throughout the midbrain and medulla was examined and characterized in pentobarbital-anesthetized rats. The TF reflex in the lightly anesthetized state is of significantly shorter latency (1.63 s vs 2.36 s) and of greater amplitude than in the unanesthetized state. Systematic mapping studies revealed that inhibition of the TF reflex could be produced from widespread areas in the midbrain and medulla. Midbrain areas having the lowest thresholds for inhibition of the TF reflex were found lateral and ventrolateral to the periaqueductal gray matter, including nucleus cuneiformis, the lateral reticular formation, and extending into the central tegmental area. In the rostral medulla, the lowest thresholds for inhibition of the TF were distributed mediolaterally across the dorsal one-third of the nucleus raphe magnus and into the adjacent nucleus reticularis gigantocellularis. Thresholds for inhibition of the TF reflex were slightly higher in the ventral nucleus raphe magnus and adjacent nucleus reticularis paragigantocellularis. Chronaxies of stimulation in the midbrain and medulla were virtually the same, indicating that the same neural elements were affected by stimulation in both brainstem areas. The thresholds of stimulation for inhibition of the TF reflex in the lightly anesthetized state were not significantly different from the thresholds of stimulation at the same midbrain sites in the awake state in the same animals. These findings contribute to a growing body of literature establishing (1) the utility of the lightly pentobarbital-anesthetized rat model for investigations of antinociceptive mechanisms and (2) the presence of multiple loci and pathways in the brainstem capable of modulating spinal nociceptive processes.