Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation.

Protein phosphatase 5 (PP5) exhibits low basal activity due to the autoinhibitory properties of its N-terminal and C-terminal domains but can be activated approximately 40-fold in vitro by polyunsaturated fatty acids. To identify residues involved in regulating PP5 activity, we performed scanning mutagenesis of its N-terminal tetratricopeptide repeat (TPR) domain and deletion mutagenesis of its C-terminal domain. Mutating residues in a groove of the TPR domain that binds to heat shock protein 90 had no effect on basal phosphatase activity. Mutation of Glu-76, however, whose side chain projects away from this groove, resulted in a 10-fold elevation of basal activity without affecting arachidonic acid-stimulated activity. Thus, the interface of the TPR domain involved in PP5 autoinhibition appears to be different from that involved in heat shock protein 90 binding. We also observed a 10-fold elevation of basal phosphatase activity upon removing the C-terminal 13 amino acids of PP5, with a concomitant 50% decrease in arachidonic acid-stimulated activity. These two effects were accounted for by two distinct amino acid deletions: deleting the four C-terminal residues (496-499) of PP5 had no effect on its activity, but removing Gln-495 elevated basal activity 10-fold. Removal of a further three amino acids had no additional effect, but deleting Asn-491 resulted in a 50% reduction in arachidonic acid-stimulated activity. Thus, Glu-76 in the TPR domain and Gln-495 at the C-terminus were implicated in maintaining the low basal activity of PP5. While the TPR domain alone has been thought to mediate fatty acid activation of PP5, our data suggest that Asn-491, near its C-terminus, may also be involved in this process.

Acupuncture for addicted patients with chronic histories of arrest. A pilot study of the Consortium Treatment Center.

Auricular acupuncture continues to gain popularity as an adjunct to substance abuse treatment. This report describes an outcomes study in a treatment center tailored to the needs of chronic repeat offenders. Thirty-seven patients who received acupuncture (AC) during the early weeks of treatment were followed for 180 days postadmission. Data were collected for four parameters: (1) program retention, (2) new arrests incurred, (3) drug-positive urinalysis results, and (4) number of days needed to progress from entry level to secondary level treatment. These data were compared to archived information from 49 no-acupuncture (NA) patients who had entered the program before acupuncture became available. Chi-square tests determined that AC patients exhibited significantly higher program retention than NA patients at 30 (p < 0.0001), 60 (p <.002), 90 (p <. 001), 120 (p <.007), and 150 (p <.031) days. At 180 days, a higher percentage of AC patients than NA patients remained in treatment, but the difference was not significant. Kaplan-Meier survival analysis determined that AC patients had significantly higher cumulative probability of remaining in treatment than did NA patients (p <.0021). In AC patients, there were decreased numbers of new arrests, drug-positive urinalysis results, and days needed to advance in treatment, but the differences were not significant. Fifty-one percent of all patients named methamphetamine as their primary drug of choice. Regardless of treatment group, methamphetamine-addicted patients exhibited significantly lower program retention than patients addicted to all other drugs (p <. 035). In methamphetamine-addicted patients, acupuncture improved program retention only up to 30 days (p <.021). These findings support addition of acupuncture to substance abuse treatment for criminal justice clients and indicate a need for acupuncture research focusing on withdrawal from methamphetamine.

Overlapping sites of tetratricopeptide repeat protein binding and chaperone activity in heat shock protein 90.

The sequential binding of different tetratricopeptide repeat (TPR) proteins to heat shock protein 90 (hsp90) is essential to its chaperone function in vivo. We have previously shown that three basic residues in the TPR domain of PP5 are required for binding to the acidic C-terminal domain of hsp90. We have now tested which acidic residues in this C-terminal domain are required for binding to three different TPR proteins as follows: PP5, FKBP52, and Hop. Mutation of Glu-729, Glu-730, and Asp-732 at the C terminus of hsp90 interfered with binding of all three TPR proteins. Mutation of Glu-720, Asp-722, Asp-723, and Asp-724 inhibited binding of FKBP52 and PP5 but not of Hop. Mutation of Glu-651 and Asp-653 did not affect binding of FKBP52 or PP5 but inhibited both Hop binding and hsp90 chaperone activity. We also found that a conserved Lys residue required for PP5 binding to hsp90 was critical for the binding of FKBP52 but not for the binding of Hop to hsp90. These results suggest distinct but overlapping binding sites on hsp90 for different TPR proteins and indicate that the binding site for Hop, which is associated with hsp90 in intermediate stages of protein folding, overlaps with a site of chaperone activity.

Hereditary hemochromatosis: should clinicians screen for this common disease?

Hereditary hemochromatosis is a serious condition of abnormal iron metabolism that is often missed until complications involving multiple organ systems occurs. It is an autosomal recessive condition primarily affecting Caucasians of Western European origin. This article discusses the pathophysiology, diagnosis, and management of this condition. Questions related to population screening are examined and recommendations made for a cost-effective screening program.

Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90.

The sequential binding of heat shock protein 90 (hsp90) to a series of tetratricopeptide repeat (TPR) proteins is critical to its function as a molecular chaperone. We have used site-directed mutagenesis to clarify the structural basis for the binding of hsp90 to the TPR domain of phosphoprotein phosphatase 5 (PP5). This TPR domain was chosen for study because its three-dimensional structure is known. We examined co-immunoprecipitation of hsp90 with wild type and mutant TPR constructs from transfected cells. Only mutations located on one face of the TPR domain affected hsp90 binding. This allowed the identification of a binding groove. Three basic residues that are highly conserved in hsp90-binding TPR proteins extend prominently into this groove. Lys-97 and Arg-101 were absolutely required for hsp90 binding, while mutation of Arg-74 diminished, but did not abrogate, hsp90 binding. Mutation of Lys-32, another conserved basic residue in the binding groove, also blocked hsp90 binding. The TPR domain of PP5 bound specifically to a 12-kDa C-terminal fragment of hsp90. This binding was reduced by mutation of acidic residues in the hsp90 fragment. These data suggest conservation, among hsp90-binding TPR proteins, of a binding groove containing basic residues that interact with acidic residues near the C terminus of hsp90.

Sialic acid-specific lectin from Tritrichomonas foetus.

A novel sialic acid-specific lectin (TFL) was isolated from Tritrichomonas foetus culture supernatant and purified by erythrocyte adsorption followed by fetuin-agarose affinity chromatography. According to gel filtration TFL is a protein of 728 kDa, different from the two sialidases of 853 and 254 kDa, secreted by T. foetus into the medium. The lectin is formed by multimeric complexes of 66 kDa subunit according to SDS-PAGE under reducing conditions. TFL is glycosylated with 4.2% of carbohydrates, half of which is represented by glucose. The lectin reacts equally with N-acetyl and N-glycolyl neuraminic acid, free, in alpha2,3- or alpha2,6-linkage. TFL has 7-fold weaker affinity to alpha2,8-linked N-acetylneuraminic acid (Neu5Ac) in colominic acid. Horse erythrocytes containing 4-O-acetyl Neu5Ac are agglutinated equally as compared to the human cells. TFL affinity to 9-O-acetyl Neu5Ac is 4-fold weaker as documented by hemagglutination inhibition with de-O-acetylated bovine submaxillary mucin, and ovine submaxillary mucin. A panel of mono- and oligosaccharides other than Neu5Ac do not inhibit TFL activity at 200 mM. The lectin does not require bivalent cations for activity, shows optimal reactivity at neutral pH and is stable at 4 degrees C. Anti-TFL antibodies identify membrane positivity on T. foetus, suggesting that the lectin functions in adhesion of the parasites. These findings, together with good stability and immunogenicity, make TFL a prospective candidate for further studies, especially in searching for efficient diagnostics and prevention of bovine trichomoniasis.

Sialic acid-specific lectin-mediated adhesion of Tritrichomonas foetus and Tritrichomonas mobilensis.

Tritrichomonas foetus is an obligate parasite of the bovine urogenital tract producing infection associated with inflammatory changes, abortion, and infertility, Tritrichomonas mobilensis was isolated from squirrel monkey colon, and symptoms involve diarrheal complications. Both tritrichomonads produced hemagglutinins with the properties of sialic acid-specific lectins. Assays on the adherence of these protozoans to Chinese hamster ovary (CHO) cells and to bovine cervical and monkey colon mucus were performed to assess the function of the lectins in adhesion. Sialic acid at concentration as low as 2 mM inhibited the adhesion to CHO cells, less effectively to the mucus. Predigestion with Clostridium perfringens sialidase prevented the adhesion to both epithelial cells and the mucus. Inhibition of endogenous sialidases with 2,3-dehydro-2-deoxy-NeuAc increased the adhesion of T. mobilensis to CHO cells. Specific anti-T. foetus lectin (TFL) and anti-T. mobilensis lectin (TML) antibodies inhibited adhesion of the trichomonads to the epithelial cells and to the mucus. TFL histochemistry disclosed the presence of lectin ligands on keratinized vaginal epithelia, cervical mucosa, and mucin and on endometrial glands and their secretions. TML histochemistry showed reactivity with the luminal membranes of colonic glandular epithelium and less with the colonic mucin. Both lectins bound to the surface membrane of CHO cells. Anti-lectin antibodies showed granular cytoplasmic and strong membrane localization of the lectins in both tritrichomonads. Although the 2 tritrichomonads have different habitats, the results indicate that both these protozoa use lectins with sialic acid specificity for adhesion to mucosal surfaces.

Abnormal activity in diabetic rat saphenous nerve.

UNLABELLED: This study was conducted to test whether abnormal spontaneous activity similar to that found after peripheral nerve trauma develops in diabetic nerve, and whether duration and/or severity of hyperglycemia affected ongoing activity. We maintained 32 diabetic BB Wistar rats on a euglycemic or hyperglycemic control regimen for 3-15 mo; 22 nondiabetic BB rats served as controls. All animals underwent acute saphenous nerve recordings. Whole nerve conduction velocities in 3- to 6-mo-old euglycemic diabetic rats were not different from controls, but 3- to 6-mo-old hyperglycemic diabetic conduction velocities were slower than in controls (P < 0.001) or euglycemic diabetic rats (P < 0.05). Compared with controls, 9- to 12-mo-old diabetic nerve conduction velocities were slower under both euglycemic (P < 0.029) and hyperglycemic (P < 0.04) regimens, but treatment groups did not differ. Combined 3- to 6-mo-old diabetic rats exhibited less resting sympathetic activity than controls under both euglycemic (P < 0.022) and hyperglycemic (P < 0.001) regimens. Sympathetic activity in 9- to 12-mo-old diabetic rats did not differ from controls. However, less sympathetic activity was found in older controls than in younger ones (P < 0.028). IN CONCLUSION: 1) saphenous nerve conduction velocity was slower in diabetic BB rats than in controls; 2) good glycemic control maintained normal conduction velocity in young adults, but the effect diminished with age; 3) resting sympathetic activity levels in young adult BB rats were lower than controls; and 4) sympathetic activity in old BB rats was diminished whether diabetes was present or not.

Patient education: recommendations regarding sunscreens, drugs, and diet.

Early recognition of melanoma is directly related to improvement in survival. Patients, therefore, must not only be educated in recognition of abnormal skin lesions, but also in proper skin examination, ultraviolet radiation protection, effect of drugs on the development of malignancies, and dietary means of promoting wellness and preventing disease. Basic patient instruction should begin at the time of diagnosis and should include all health care team members to assure patient comprehension and compliance with recommendations.

Tourniquet-induced limb ischemia: a neurophysiologic animal model.

A rat model of tourniquet-induced ischemia was created to observe the changes in sciatic afferent neuronal activity associated with prolonged tourniquet inflation on the hind leg. The sciatic nerve was divided in the proximal thigh and a two-electrode microfilament recording technique and signal averaging computer were used to survey afferent neuronal activity prior to and after tourniquet inflation. This method was able to determine both firing rate and conduction velocity of spontaneously active or mechanically sensitive nerve fibers. In 14 rats observed prior to tourniquet inflation there was much spontaneous activity. These fibers all had rapid conduction velocities (30 +/- 6.9 m/s) (mean +/- SD) and firing rates (16.3 +/- 1.9 H). All fibers could be stimulated by movement of distal joints or by probing the skin of the leg. After tourniquet inflation, a pressure-induced conduction block occurred stopping all spontaneous and mechanically induced activity. After a short interval, (55 +/- 16 min) a different group of spontaneously active fibers were observed that had both slow conduction (2.04 +/- 0.77 m/s) firing rates (0.54 +/- 0.9 H). These fibers did not respond to mechanical stimulation of the limb distal to the tourniquet, or local anesthetic or cold block of the nerve distal to the tourniquet. Blockade of the sciatic nerve just proximal to the tourniquet and deflation of the tourniquet did abolish activity in these fibers. In ten separate rats in which tourniquets were placed but no surgical incision made, mean arterial blood pressure rose significantly after tourniquet inflation. With tourniquet deflation, blood pressure fell significantly from levels observed during tourniquet inflation.(ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine restriction as initial treatment for breast pain.

The effects of methylxanthines (caffeine, theophylline and theobromine) on the symptoms associated with fibrocystic breast disease were studied in 147 patients. Disease was documented by mammography, physical examination and clinical symptoms. Only those individuals with breast pain (n = 138) were included in the study. Questionnaires were presented and explained to all patients by the same nurse examiner. Patients reported their degree of caffeine consumption as either light (two cups per day or less of caffeine-containing beverages or foods), moderate (more than two cups, but less than six cups per day), or heavy (six cups per day or more of caffeine-containing products). They additionally reported breast pain as mild, moderate or severe. Past medical and family histories were reported as well as medication intake. All patients were counseled to abstain from or reduce caffeine consumption and were given a list of commonly used caffeine-containing products. The results at the end of one year indicated that compliance was high, with 113 patients (81.9 percent) reducing their caffeine intake substantially and, of those, 69 (61 percent) reporting a decrease or absence of breast pain. This study supports the findings of others in that caffeine restriction is an effective means of management of breast pain associated with fibrocystic disease.

Spontaneous activity in afferent and efferent fibers after chronic axotomy: response to potassium channel blockade.

Distally propagating spontaneous impulses in acutely and chronically cut rat saphenous nerve were examined to determine (1) the origin(s) of the activity, (2) the fiber types involved, and (3) whether the activity was affected by potassium channel blockade. Under deep pentobarbital anesthesia, six male Sprague-Dawley rats underwent L3 cauda equina section, then unilateral saphenous axotomy. The nerve was then dissected into 30-50 microfilaments and surveyed for spontaneous activity using a modification of the microfilament recording method. Afterward, the nerve was cut back, and a potassium channel blocking agent (gallamine) was administered. The axonal activity was once again surveyed in the same fashion. Twenty-eight rats underwent unilateral saphenous axotomy 1-8 weeks prior to similar recordings, and the neuroma was excised just before microfilament dissection. Spontaneous discharges in these preparations originated from three foci: (1) antidromic activity from in-continuity dorsal root ganglia (DRG), (2) orthodromic activity from sympathetic neurons, and (3) antidromic activation of dichotomizing afferent axons in the peripheral nerve. There was significantly more antidromic activity from DRG in rats with prior axotomies than in control animals (t = 2.38; p less than 0.025), and gallamine produced a significant increase in DRG activity in the chronically lesioned nerve (t = 2.43; p less than 0.005), but not in acutely lesioned controls. However, most of the spontaneous activity in these preparations was from sympathetic efferents. This activity was decreased significantly by chronic axotomy (t = 2.635; p less than 0.01), and it was not affected by potassium channel blockade with gallamine. In two microfilaments, spontaneous antidromic action potentials were observed in conjunction with a clear receptive field on blood vessels in the nearby fascia. Both of these presumably dichotomized axons were found in acutely cut nerve, thus were not the result of retrograde sprouting from a neuroma. It was concluded that (1) chronic axotomy of sensory afferents produced ectopic activity in their respective DRG, (2) gallamine administration increased spontaneous activity from DRG in chronically axotomized rats, (3) ongoing sympathetic efferent activity in rat saphenous nerve was decreased by distal axotomy for up to 8 weeks, and (4) rare branched sensory afferents occasionally exhibit spontaneous activity.

Has the amount of spontaneous electrical activity in experimental neuromas been overestimated?

Previous studies of experimental neuromas have indicated that some axons terminating in the neuroma exhibit both spontaneous and mechanosensitive discharges. Since these spontaneous discharges appear to occur in potentially nociceptive axons (A delta and C fibers), it has been speculated that this activity may relate to pain that occurs after peripheral nerve injury. Recent results from our laboratory have revealed several possible sources of error in prior electrophysiological studies of neuromas. Most notably, gallamine, a muscle-paralyzing agent that has been used in the majority of previous studies of experimental neuromas, has profound potassium-channel-blocking properties that may increase spontaneous activity in damaged axons. The present study was conducted to re-evaluate the incidence of spontaneous activity in experimental neuromas, and the fiber types involved in these discharges. A group of 44 male Sprague-Dawley rats underwent unilateral saphenous axotomy 1-8 weeks prior to acute neurophysiological recording experiments, and 6 additional rats underwent acute control recording procedures only. Recording was performed in all animals using a modification of the microfilament recording technique to determine the conduction velocities (CVs) and origins of spontaneously discharging axons. A thorough search for spontaneous discharges was made in each nerve both before and after the administration of gallamine. Spontaneous activity was rare in acutely severed saphenous nerve and was not significantly affected by gallamine administration. In rats with 1- to 4-week-old experimental saphenous neuromas, spontaneous activity was rare but was increased by a factor of 12.75 after gallamine treatment. Gallamine administration produced significantly more of both A alpha beta and A delta activity, compared to control recordings. No spontaneous C-fiber activity was found originating in neuromas either before or after gallamine. C-fiber spontaneous discharges in the apparently isolated saphenous nerve segment had receptive fields in fascia, superficial vasculature, and hairy skin of the medial hindlimb. Our conclusions are as follows: (1) Neuromas exhibit only rare spontaneous discharges unless exposed to potassium-channel-blocking agents; (2) all C-fiber activity recorded in saphenous nerve with a distal neuroma is derived from vascular, fascial, and other receptive fields rather than from the neuroma; (3) these data are consistent with known clinical phenomena in that neuromas are not usually spontaneously painful.

Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats. A possible mechanism of chronic diabetic neuropathic pain.

The mechanism of painful diabetic neuropathy remains unknown. Spontaneous activity in nociceptive primary afferents has been implicated in the genesis of chronic pain due to peripheral nerve injury, and diabetic axonopathy shares some histologic features with traumatic neuropathy. We hypothesized that spontaneous hyperactivity of nociceptive neurons might represent the neurophysiologic mechanism of diabetic neuropathic pain. To test this, we examined the spontaneous activity of primary afferent axons from diabetic BB/Wistar and normal Wistar rat saphenous nerves isolated from central and peripheral connections. Microfilament recordings from diabetic nerves showed a significantly higher incidence of spontaneous discharges in comparison to normal nerves. Furthermore, this spontaneous hyperactivity occurred almost exclusively in potentially nociceptive C-fibers. We conclude that in the diabetic BB/Wistar rat, spontaneous impulses are generated in potential nociceptive primary afferent neurons, and that this may represent the mechanism of chronic diabetic neuropathic pain.

Glycerol neurolysis: neurophysiological effects of topical glycerol application on rat saphenous nerve.

The effect of topical glycerol application on normal and previously injured saphenous nerves was tested in 20 Sprague-Dawley rats. Anhydrous glycerol treatment of five normal nerves showed a rapid loss of C-fiber conduction within 5 minutes of application, while after 10 to 30 minutes, a complete conduction blockade in all fiber types was produced. The effect of anhydrous glycerol on both spontaneous firing from the neuroma and impulse propagation within the nerve was examined in 11 rats that had undergone saphenous neurotomy 7 days previously. In these animals, cessation of spontaneous action potential production from the neuroma was the earliest electrophysiological change noted, followed by loss first of C-fiber, then of A-fiber conduction. Graded concentrations of glycerol (25%, 50%, 75%, and 100%) were used in four rats with saphenous neuromas, which allowed selective blockade of spontaneous action potential generation and C-fiber conduction with minimal effect on A-fibers. The neurophysiological mechanism of glycerol neurolysis appears to be a nonspecific conduction blockade of large and small fibers, which is established within minutes of its application. Spontaneous firing within damaged axons, which may play a role in a variety of cranial and peripheral nerve sensorimotor syndromes, is also exquisitely sensitive to glycerol application.

Effects of potassium channel-blocking agents on spontaneous discharges from neuromas in rats.

Thirty-five Sprague-Dawley rats with saphenous neuromas underwent acute microfilament recording in the proximal nerve. The effect of the potassium channel-blocking agents, tetraethylammonium bromide (TEA) and 4-aminopyridine, on spontaneous activity in A fibers terminating in the neuroma was observed. The effects of gallamine were also tested. Of the two channel-blocking agents, TEA reliably increased spontaneous firing in active fibers and initiated spontaneous activity in some fibers with no spontaneous baseline discharge. 4-Aminopyridine had no effect on baseline activity of either spontaneously active or quiescent fibers: however, it inhibited spontaneous activity induced by prior TEA treatment. Gallamine application produced effects similar to TEA in that spontaneous activity was dramatically increased. These results imply that a tonic potassium conductance is present in regenerating fibers in the neuroma and that this conductance moderates the tendency toward hyperexcitability and spontaneous firing. Spontaneous activity in nociceptive afferent fibers may represent the mechanism of chronic pain and paresthesias that often accompany peripheral nerve injury. These results suggest that agents which either increase potassium conductance or selectively inhibit the sodium current in regenerating axons might be effective in the treatment of these chronic pain syndromes.

Spontaneous activity of ventral root axons following peripheral nerve injury.

In 18 Sprague-Dawley rats, the left sciatic nerve was divided at the mid-femur level. Seven to 9 days later, microfilament recordings were made from the ipsilateral L-5 ventral root. Spontaneous activity in the ventral root, ranging from 0.1 to 6.1 Hz, was recorded in 12 of the 18 animals. Conduction velocity determinations showed this activity to be in A-beta and A-delta fibers. Recordings in 10 normal L-5 ventral roots from five control rats showed no spontaneous activity. In the rats with sciatic nerve division, the ongoing discharge appeared to originate in the cut end of the nerve since mechanical stimulation of the neuroma produced synchronous ventral root activity. Furthermore, cooling of the neuroma inhibited the spontaneous discharge, whereas with rewarming it returned. Spontaneous ventral root activity was also increased by systemic application of epinephrine. This activity was qualitatively similar to spontaneous activity that has been recorded in dorsal root microfilaments after peripheral nerve injury. The observation of an ongoing discharge in potentially nociceptive ventral root axons subsequent to nerve injury may be relevant to the mechanism of chronic pain of peripheral origin.

Neurophysiological effects of capsaicin.

Data obtained from neonatally treated rats are fairly consistent. However, there is disagreement as to whether mechanical and thermal nociceptive thresholds are elevated or unchanged in this group. There are at least two major areas of disagreement in adult animal capsaicin research. Behavioral data are extremely variable. The thermal nociceptive threshold after systemic capsaicin has been reported to be both raised and lowered. After intrathecal capsaicin injection, the thermal nociceptive threshold was reported raised, but onset and duration of responses varied and some animals exhibited no changes. Capsaicin application to peripheral nerve, however, drastically increased thermal threshold. Mechanical pain threshold has been reported both increased and unchanged after systemic capsaicin treatment and unchanged after intrathecal injection. Obviously, capsaicin's effects upon pain perception are not fully understood. Although lower on the phylogenetic scale than many mammals, rodents exhibit complex individualistic behavior. Lower vertebrates may eventually provide more simple behavioral models for pain tolerance. Investigators also disagree as to whether C fibres can conduct action potentials after local capsaicin application. C fibre conduction was reported unaffected by capsaicin in an acute preparation and for 13-21 days after treatment. On the other hand, C fibre compound action potentials have been reported diminished for up to 2 h after capsaicin application. Additional conduction impairment studies will be useful in comparing peripheral and intrathecal capsaicin application. There is general agreement that, allowing for variation in dosages and route of administration, capsaicin causes central and peripheral C fibre damage, though never as extensive in adults as in neonates. Neonatal capsaicin treatment (always s.c.) results in destruction of C and some A delta fibres and their central terminals. Capsaicin causes degeneration of C terminals in the adult CNS only when applied centrally. In both neonates and adults, s.c. capsaicin depletes the putative 'pain' peptide neurotransmitter, SP, from peripheral and sensory neurons and the tissues they innervate but not from the gut. Capsaicin-induced SP depletion in neonates is permanent. Systemic administration to adult depleted SP from much the same areas as observed in neonates, but all areas but the medulla exhibited a slow, regional recovery. Intraventricular injection of capsaicin depleted SP in the adult medulla only, while other SP-containing areas affected by systemic injection remained intact.(ABSTRACT TRUNCATED AT 400 WORDS)