Effects of desipramine maintenance on cocaine self-administration by humans

Six research volunteers with histories of cocaine use were tested in a cocaine choice paradigm to investigate the effects of desipramine maintenance on cocaine-taking behavior. Subjects were allowed to self-administer i.v. saline or cocaine (8, 16 or 32 mg) in daily 3-hr sessions to establish baseline levels of self-administration, self-reported effects of the drug and changes in heart rate and blood pressure. Each subject was then maintained on daily doses of desipramine for 3 to 4 weeks, after which a second cocaine self-administration dose-response curve was generated under desipramine maintenance. This maintenance had no effect on cocaine self-administration. There was, however, a significant increase in heart rate and blood pressure during desipramine maintenance. Desipramine maintenance also resulted in a change in the profile of cocaine's self-reported effects. In some cases (e.g., Arousal and Vigor on the Profile of Mood States, Benzedrine Group scale on the Addiction Research Center Inventory), reports of cocaine's effects were significantly reduced under conditions of desipramine maintenance, and in others (e.g., Anxiety, Anger and Confusion on the Profile of Mood States), those reports were significantly increased. Furthermore, there was a significant decrease in subjects response to an "I want cocaine" question while under desipramine maintenance. The data suggest that desipramine does not affect the reinforcing properties of cocaine, but may interfere with its other stimulus properties. Furthermore, the cardiovascular effects of desipramine appear to have the potential for toxicity when that drug is administered in combination with cocaine.     

Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans.

Animal studies have demonstrated that activation of the baroreflex by increases in arterial pressure inhibits cardiovascular and ventilatory responses to activation of peripheral chemoreceptors (PC) with hypoxia. In this study, we examined the influences of baroreflex activation on the sympathetic response to stimulation of PC and central chemoreceptors in humans. PC were stimulated by hypoxia (10% O2/90% N2) (n = 6) and central chemoreceptors by hypercapnia (7% CO2/93% O2) (n = 6). Responses to a cold pressor stimulus were also obtained as an internal reflex control to determine the selectivity of the interactive influence of baroreflex activation. Baroreflex activation was achieved by raising mean blood pressure by greater than 10 mmHg with intravenous infusion of phenylephrine (PE). Sympathetic nerve activity (SNA) to muscle was recorded from a peroneal nerve (microneurography). During hypoxia alone, SNA increased from 255 +/- 92 to 354 +/- 107 U/min (P less than 0.05). During PE alone, mean blood pressure increased and SNA decreased to 87 +/- 45 U/min (P less than 0.05). With hypoxia during baroreflex activation with PE, SNA did not increase (50 +/- 23 U/min). During hypercapnia alone, SNA increased from 116 +/- 39 to 234 +/- 72 U/min (P less than 0.01). Hypercapnia during baroreflex activation with PE increased SNA from 32 +/- 25 U/min during PE alone to 61 +/- 26 U/min during hypercapnia and PE (P less than 0.05). Like hypercapnia (but unlike hypoxia) the cold pressor test also increased SNA during PE. We conclude that baroreflex activation selectively abolishes the SNA response to hypoxia but not to hypercapnia or the cold pressor test. The inhibitory interaction of the baroreflex and the peripheral chemoreflex may be explained by convergence of baroreceptor and peripheral chemoreceptor afferents on neurons in the medulla.     

Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans.

We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.     

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.     

Sympathetic nerve activity to amputated lower leg in humans. Evidence of altered skin vasoconstrictor discharge

Transection of a peripheral nerve in the cat is known to cause a regional change in sympathetic impulse pattern. Our aim was to determine whether microneurography can be used to study sympathetic activity in the transected nerve of human amputees, and whether any such activity shows an abnormal pattern similar to that observed in the cat. Seven successful sympathetic recording sessions were performed in the peroneal nerve of four subjects with posttraumatic transtibial leg amputation; one of them was studied on four occasions. Muscle nerve sympathetic activity (MSA) was detected in all four subjects. Skin nerve sympathetic activity (SSA) was found in one patient only, but on three occasions. It was more difficult to obtain high quality sympathetic recordings than for intact nerves, particularly in patients amputated many years before our studies. MSA showed a qualitatively normal pattern at rest and during various manoeuvres. In three recordings from skin nerve fascicles without innervation zone, SSA displayed normal characteristics at room temperature and qualitatively normal responses to arousal stimuli and various manoeuvres. During body cooling there was an abnormal shift in SSA pattern with a reduction in burst duration instead of the increase occurring normally. Cardiac rhythmicity of SSA was more pronounced during body cooling than during body heating. This is also a reversal of the normal pattern. The abnormal SSA pattern during body cooling suggests increased baroreflex regulation of cutaneous vasoconstrictor neurones, similar to the change after nerve transection in the cat. This is the first time that human nerve recordings support the hypothesis of a regional alteration in sympathetic impulse pattern following a nerve lesion. The implications of this phenomenon for pain conditions remains to be explored; our patients did not suffer from phantom or stump pain.     

Self-administration of cocaine by humans: choice between smoked and intravenous cocaine.

Ten healthy adult male research volunteers reporting smoked and i.v. cocaine use resided on a Clinical Research Center for 2 weeks and participated in nine daily sessions. A session consisted of seven choice trials. The first two trials were sampling trials in which subjects received one dose each of i.v. cocaine hydrochloride (0, 16 and 32 mg) and smoked cocaine base (0, 25 and 50 mg). Each of the remaining five trials was a choice trial in which subjects could choose to self-administer either of the doses from the initial two trials. Subjects 1) reliably chose active doses of cocaine compared to placebo, 2) chose to self-administer the low-smoked cocaine dose about as often as either the low or high i.v. cocaine doses and 3) reliably chose the high-smoked cocaine dose when compared to either active i.v. dose. With few exceptions, both low doses and high doses produced similar subjective and cardiovascular effects after the initial dose, regardless of the route of administration. This suggests that initial effects were not predictive of subsequent choice. Cumulative doses of smoked cocaine increased scores on a number of subjective-effects measures that were not similarly increased by cumulative doses of i.v. cocaine. These differences were predictive of smoked cocaine self-administration. After session ratings of drug "Liking" and "Quality" differentiated smoked from i.v. cocaine, reflecting route choice. However, there were no significant differences between these ratings for low and high doses. These results provide information about the relationship between subjective drug effects and drug self-administration, and demonstrate the utility of a choice procedure in analyzing these relationships.     

Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans.

We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.     

Effects of clonidine on renal sympathetic nerve activity and norepinephrine spillover

The antihypertensive action of clonidine (CLO) depends mainly on decreased release of the sympathetic neurotransmitter, norepinephrine (NE), at vascular neuroeffector junctions. The decreased release can be due to stimulation of alpha-2 adrenoceptors or other receptors in the brain or due to stimulation of presynaptic inhibitory alpha-2 adrenoceptors on sympathetic nerve endings. To compare central and peripheral contributions to the depressor action of CLO, renal sympathetic nerve activity (RSNA) and renal spillover of NE (RNEs) were measured at baseline and during reflexive increases in RSNA evoked by nitroprusside-induced hypotension (27, 50 and 105 micrograms/kg/min) before and after CLO treatment in adrenal-demedullated, anesthetized rats. Administration of CLO decreased RSNA by 52 +/- 8% and RNEs by 32 +/- 13% (means +/- S.E.M.). At levels of RSNA less than 50% above control, there were no significant changes in RNEs; above this level of activity RNEs increased, regardless of CLO treatment. CLO treatment did not alter significantly the relationship between increases in RSNA and in RNEs during nitroprusside-induced hypotension. The results suggest that in neurologically intact, anesthetized animals, CLO decreases renal NE release mainly by inhibiting sympathetic outflow, with little if any peripheral presynaptic action.     

Acute tolerance to cocaine in humans

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half-life of 31 +/- 13 (mean +/- SD) minutes toward a plateau at 33% +/- 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration-effect relationship.     

Procainamide inhibits sympathetic nerve activity in rabbits.

Procainamide has been used extensively for the treatment of ventricular arrhythmias. It is widely held that the sympathetic nervous system plays an important role in the pathogenesis of ventricular arrhythmias. We investigated the possibility that procainamide has effects on the sympathetic nervous system by determining the responses to procainamide of postganglionic renal and preganglionic lumbar nerve activity in rabbits with sinoaortic and vagal denervation. Bolus administration of procainamide (3, 7, and 15 mg/kg) resulted in dose-dependent decreases in renal sympathetic nerve activity (26%, 38%, and 57%, respectively). These boluses resulted in plasma levels of procainamide of 13.3, 23.6, and 41.7 micrograms/ml, respectively. The same doses of procainamide resulted in decreases in lumbar nerve activity of 36%, 36%, and 41%, respectively. In a separate group of rabbits pretreated with hexamethonium (n = 8), 15 mg/kg procainamide reduced lumbar nerve traffic by 38%. Infusion of procainamide at 1 mg/kg/min over 20 minutes (n = 9) resulted in a decrease in renal sympathetic nerve activity of 20% with a plasma level of 11 micrograms/ml. Sham-treated rabbits (n = 8) exhibited an 18% increase in traffic over a comparable period of time. We conclude that procainamide inhibits lumbar and renal sympathetic nerve activity through effects on the brain or spinal cord. The influence of procainamide on sympathetic nerve activity may contribute importantly to its efficacy in the therapy of ventricular arrhythmias.     

Effects of sympathetic inhibition on exertional dyspnoea, ventilatory and metabolic responses to exercise in normotensive humans.

Augmentation of circulating noradrenaline concentration stimulates ventilation during the initial stages of exercise and this is accompanied by an increased sensation of dyspnoea and exertion. This previous study [Clark, Galloway, MacFarlane, Henderson, Aitchison and McMurray (1997) Eur. Heart J. 18, 1829-1833] suggested a link between dyspnoea, which commonly limits exercise tolerance in heart failure patients, and high circulating noradrenaline concentration in these patients. The present study investigated this relationship further using sympathetic inhibition. Ten healthy normotensive males performed 10 min of submaximal cycling exercise at approx. 70% of maximal oxygen uptake per min (VO2max) on three occasions one week apart. The first of these sessions was a familiarization session and the other two were experimental study days. On each of the study days, subjects attended the laboratory in the morning after an overnight fast and, following a resting blood sample, were administered placebo or moxonidine (0.4 mg) in a double blind cross-over design. After a 90-min absorption period, subjects undertook the exercise task. Blood was drawn, expired gas was analysed breath by breath, blood pressure, heart rate and ratings of perceived dyspnoea and exertion were obtained. Moxonidine treatment significantly reduced plasma noradrenaline concentration (P < 0.01), mean arterial pressure (P < 0.01), and blood glycerol concentration (P < 0.05), but no differences were observed in heart rate, the ventilatory response to exercise or subjective ratings of dyspnoea and exertion. This study indicates that reducing sympathetic activity does not affect ventilation, perceived dyspnoea or perceived exertion in normotensive males. Therefore it can be concluded that reducing sympathetic activity may not be an appropriate strategy to help reduce perceived dyspnoea.     

高脂血症对大鼠心肌梗死后交感神经重构的影响及机制探讨

目的:探讨高脂血症对大鼠心肌梗死后交感神经重构的影响.方法:32只SD大鼠随机分为A组(假手术组)、B组(高脂血症组)、C组(心梗组)和D组(心梗合并高脂血症组).免疫组化法检测梗死周边区生长相关蛋白-43(GAP-43)和酪氨酸羟化酶(TH)阳性神经纤维分布和密度.Western blot方法检测神经生长因子(NGF)和白介素-1β(IL-1β)蛋白表达.生化法检测氧化应激相关指标.结果:心肌梗死和高脂血症均可导致梗死周边区域GAP-43和TH阳性神经纤维密度显著增加(均P<0.05),并伴随着NGF、IL-1β蛋白表达的上调和氧化应激水平的增高,且两因素间存在交互作用(均P<0.05).GAP-43和TH阳性神经纤维密度与NGF、IL-1β蛋白水平及氧化应激呈良好的正相关性(均P<0.05).结论:高脂血症可以加剧心肌梗死大鼠交感神经重构,其机制与氧化应激和IL-1β释放增加导致NGF表达上调相关.     

Effects of nonpulsatile left heart bypass on renal sympathetic nerve activity in rabbits

To determine the effects of nonpulsatile left heart bypass (LHB) on sympathetic nerve activity the renal sympathetic nerve activity (RSNA) was directly measured in rabbits. In anaesthetized rabbits (n=6), LHB was instituted with a centrifugal pump. Before and during LHB, heart rate (HR), arterial pressure (AP), central venous pressure (CVP), left atrial pressure (LAP) and spike counts of RSNA were measured. After bilateral vagotomy (section of the afferent inputs of the cardiac reflex arc) the same parameters were measured before and during LHB. Data were obtained at the same level of mean AP before and during LHB. Mean AP and CVP were not changed by LHB before and after vagotomy. LAP was significantly decreased by LHB before and after vagotomy. RSNA and HR were not significantly changed by LHB before and after vagotomy. Our results clarify the complex baroreflex control during nonpulsatile LHB and indicate that RSNA is not altered by LHB.     

Neuronal re-uptake of noradrenaline by sympathetic nerves in humans.

1. Plasma concentrations of [3H]dihydroxyphenylglycol, the intraneuronal metabolite of noradrenaline, were examined during intravenous infusion of [3H]noradrenaline in 43 subjects, to assess the nature of its formation. Noradrenaline re-uptake by sympathetic nerves was estimated in 11 subjects from the effects of neuronal uptake blockade with desipramine on noradrenaline clearance and plasma concentrations of [3H]dihydroxyphenylglycol and endogenous dihydroxyphenylglycol. In seven subjects noradrenaline re-uptake and spillover into plasma were examined before and during mental arithmetic or handgrip exercise. 2. During infusion of [3H]noradrenaline, plasma [3H]dihydroxyphenylglycol increased progressively, indicating its formation from previously stored [3H]noradrenaline leaking from vesicles as well as from [3H]noradrenaline metabolism immediately after removal into sympathetic nerves. Thus, to estimate noradrenaline re-uptake, the amount of [3H]dihydroxyphenylglycol derived from [3H]noradrenaline metabolized immediately after removal into the sympathetic axoplasm must be isolated from that derived from [3H]noradrenaline sequestered into vesicles. 3. At rest in the supine position the rate of noradrenaline re-uptake was 474 +/- 122 pmol min-1 kg-1, 9.5-fold higher than the rate of spillover of noradrenaline into plasma (49.6 +/- 6.4 pmol min-1 kg-1). Noradrenaline re-uptake and spillover into plasma were both increased during mental arithmetic and isometric handgrip exercise.     

The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache

The administration of nitroderivatives in cluster headache (CH) sufferers is the most reproducible experimental paradigm to induce spontaneous-like pain attacks. Previous uncontrolled studies have reported that the local use of anaesthetic agents in the area of the sphenopalatine fossa is able to extinguish nitroglycerin (NTG)-induced pain in CH. The present study, carried out according to a double-blind placebo-controlled design, included 15 CH patients, six with episodic CH (mean +/- SD age of 36.8+/-5.6 years), and nine with chronic CH (37.8+/-10.4 years). Patients had undergone a standard NTG test (0.9 mg sublingually), during which the intensity of pain was scored using a visuoanalogic scale (VAS, range 0-10). Nine patients (two with the episodic form, seven with the chronic form) experienced a typical, spontaneous-like attack on the usual side, occurring in all cases within 45 min. In these patients, the test was repeated with an interval of 2 days, and once pain intensity reached 5 on the VAS, a 10% solution of cocaine hydrochloride (1 ml, mean amount per application 40-50 mg), or 10% lidocaine (1 ml), or saline was applied using a cotton swab in the area corresponding to the sphenopalatine fossa, under anterior rhinoscopy. This was done in both the symptomatic and the non-symptomatic side, for 5 min. Treatments were always performed randomly, in separate sessions. All patients responded promptly to both anaesthetic agents, with complete cessation of induced pain occurring after 31.3+/-13.1 min for cocaine and 37.0+/-7.8 min for lidocaine (M+/-SD). In the case of saline application, pain severity increased thereafter, and extinction of the provoked attacks occurred with a latency of 59.3+/-12.3 min (P<0.01 and P<0.01 vs. cocaine and lidocaine, respectively, Mann-Whitney U-test). While further suggesting that the sphenopalatine ganglion participates in the mechanisms of pain, these findings indicate that the local administration of the anaesthetic agents cocaine and lidocaine is effective on NTG-induced CH attacks, and may be used in the symptomatic treatment of this disorder.     

Effects of central sympathetic inhibition on heart rate variability during steady-state exercise in healthy humans

The profound reduction in heart rate variability (HRV) that occurs during exercise is thought to be, at least in part, the result of sympathetic nervous system activation. Moxonidine is a centrally acting anti-sympathetic drug, which suppresses sympathetic nervous system outflow by stimulation of central imidazoline receptors located in the rostral ventro-lateral medulla. This study was designed to investigate the combined effects of central sympathetic inhibition with moxonidine and steady-dynamic exercise on HRV. Ten normal males participated in a double-blind cross-over study, taking either placebo or 0.4 mg of moxonidine. The subjects were studied at rest and during steady-state exercise. HRV was measured considering both time and frequency domain parameters. As a non-linear measure, the Poincaré scatter-plot was measured and analysed quantitatively. Ventilation and gas exchange were also measured during exercise. In addition, plasma catecholamines were measured at rest and during exercise. The only parameter changed, at rest, by moxonidine was the blood pressure which was reduced. During exercise, moxonidine reduced plasma noradrenaline (NA), compared with the placebo (P<0.01). The only change observed in HRV during exercise was a significant reduction of the continuous long-term standard deviation (SD2) of the Poincaré scatter-plot of the R-R interval (P<0.05). However, the potential and prognostic significance of this result needs to be further assessed.     

Enadoline and butorphanol: evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans

Preclinical studies have demonstrated that kappa-opioid agonists can attenuate the neurochemical and behavioral effects of cocaine that are related to its reinforcing efficacy, suggesting that kappa-agonists may serve as pharmacotherapies for cocaine dependence. This 8-week inpatient study examined the ability of enadoline, a selective and high-efficacy kappa-agonist, and butorphanol, a mixed agonist with intermediate efficacy at both mu- and kappa-receptors, to reduce the direct pharmacodynamic effects and self-administration of intravenous cocaine in humans (n = 8). Acute doses of intramuscular enadoline (20, 40, and 80 microg/kg), butorphanol (1.5, 3, and 6 mg/70 kg) and placebo were examined separately as pretreatments during each of three test sessions with cocaine in a constrained random order. A cocaine dose-effect session (0, 20, and 40 mg cocaine i.v., 1 h apart) examined direct pharmacodynamic interactions on subjective and physiological indices; self-administration sessions examined choice behavior for cocaine (40 mg i.v. for six trials) versus money 1) in the presence of a sample cocaine dose with money choices presented in ascending value, and 2) in the absence of a sample dose with money choices presented in descending values. Enadoline (80 microg/70 kg) significantly (p < 0.05) reduced some of the positive subjective effects of cocaine (e.g., ratings of "high"), while butorphanol failed to modify subjective responses. Both agents were safely tolerated in combination with cocaine without adverse physiological responses. Cocaine self-administration was significantly greater across all pretreatment conditions when the sample dose was given and ascending money choices were used. Enadoline and butorphanol failed to modify cocaine self-administration. These data suggest that these kappa-agonists may be safely administered in the presence of cocaine but do not produce significant attenuation of cocaine's direct effects or self-administration under these acute dosing conditions.     

Acute myocardial infarction following the use of intranasal anesthetic cocaine

The use of cocaine has become largely obsolete in modern medical practice; however, it is still used by otolaryngologists for topical anesthesia in head and neck surgeries. We present the case of a 68-year-old woman who developed a myocardial infarction after the use of topical cocaine during nasal sinus surgery, and review the literature regarding the use of cocaine as a topical anesthetic in otolaryngologic practice. Awareness is raised of a possible complication of myocardial infarction following topical cocaine anesthetic use.     

Cranial manipulation can alter sleep latency and sympathetic nerve activity in humans: a pilot study

OBJECTIVE: To determine if cranial manipulation is associated with altered sleep latency. Furthermore, we investigated the effects of cranial manipulation on muscle sympathetic nerve activity (MSNA) as a potential mechanism for altered sleep latency. DESIGN: Randomized block design with repeated measures. SETTING: The Integrative Physiology and Manipulative Medicine Departments, University of North Texas Health Science Center, Fort Worth, TX. SUBJECTS: Twenty (20) healthy volunteers (12 male, 8 female; age range, 22-35 years) participated in this investigation. INTERVENTIONS: Subjects were exposed to 3 randomly ordered treatments: compression of the fourth ventricle (CV4), CV4 sham (simple touch), and control (no treatment). OUTCOME MEASURES: Sleep latency was assessed during each of the treatments in 11 subjects, using the standard Multiple Sleep Latency Test protocol. Conversely, directly recorded efferent MSNA was measured during each of the treatments in the remaining 9 subjects, using standard microneurographic technique. RESULTS: Sleep latency during the CV4 trial was decreased when compared to both the CV4 sham or control trials (p < 0.05). MSNA during the CV4-induced temporary halt of the cranial rhythmic impulse (stillpoint) was decreased when compared to prestillpoint MSNA (p < 0.01). During the CV4 sham and control trials MSNA was not different between CV4 time-matched measurements (p > 0.05). Moreover, the change in MSNA prestillpoint to stillpoint during the CV4 trial was different compared to the CV4 sham and control trials (p < 0.05). However, this change in MSNA was similar between the CV4 sham and control trials (p > 0.80). CONCLUSIONS: The current study is the first to demonstrate that cranial manipulation, specifically the CV4 technique, can alter sleep latency and directly measured MSNA in healthy humans. These findings provide important insight into the possible physiologic effects of cranial manipulation. However, the mechanisms behind these changes remain unclear.