Neuroplasticity in the sparing or deterioration of function after early olfactory tract lesions.

Mating behavior in male hamsters depends on the sense of smell. Thus, complete transection of the lateral olfactory tract in adults eliminates mating. If the cut is made early in life, however, mating is spared. Partial section of the tract in adults does not affect mating, but similar cuts in the neonate lead to impaired mating performance later in life. Observed postsurgical rearrangements in the connections of axons in the lateral olfactory tract may explain both the sparing and the deterioration of function.

Intraneuronal substance P contributes to the severity of experimental arthritis.

There is evidence that substance P is a peptide neurotransmitter of some unmyelinated primary afferent nociceptors and that its release from the peripheral terminals of primary afferent fibers mediates neurogenic inflammation. The investigators examined whether substance P also contributes to the severity of adjuvant-induced arthritis, an inflammatory disease in rats. They found that, in the rat, joints that developed more severe arthritis (ankles) were more densely innervated by substance P-containing primary afferent neurons than were joints that developed less severe arthritis (knees). Infusion of substance P into the knee increased the severity of arthritis; injection of a substance P receptor antagonist did not. These results suggest a significant physiological difference between joints that develop mild and severe arthritis and indicate that release of intraneuronal substance P in joints contributes to the severity of the arthritis.

Appendicular fracture repair in dogs using the locking compression plate system: 47 cases.

The locking compression plate (LCP) has combination screw holes, making it possible to use the implant in three different ways; as a pure internal fixator using locking head screws, as a conventional compression plate using compression screws, or as a hybrid of the two. The experience with the LCP system in veterinary fracture repair is limited. The objective of this study was to evaluate the outcome of appendicular fractures in dogs, which were repaired with the LCP system combined with less invasive surgical techniques. Medical records and radiographs from 47 dogs were studied retrospectively. Thirty-four percent of the fractures were simple, six percent wedge and 60% comminuted fractures of the humerus (11 %), radius and ulna (30 %), femur (34 %) and of the tibia and fibula (25 %). The fractures were treated using the LCP as an internal fixator; in some cases as a plate and rod construct. Forty-six of 47 fractures reached radiographic union. Mean healing time of the fractures was seven weeks (95% confidence interval from 5.8 to 8.3 weeks). There were statistically significant differences in healing time between juvenile (age under one year) and adults. Complications in the form of implant failures and infections were encountered in approximately 11% of the cases. All implant failures were due to surgical errors. The LCP system in combination with a less invasive surgical approach was found advantageous in comminuted fractures where the LCP was used as a bridging plate, in situations when exact plate contouring was difficult, and when other implants prevented the use of bi-cortical screws.

Mesopontine tegmental anesthesia area projects independently to the rostromedial medulla and to the spinal cord.

General anesthetics are presumed to act in a distributed manner throughout the CNS. However, we found that microinjection of GABAA-receptor (GABAA-R) active anesthetics into a restricted locus in the rat brainstem, the mesopontine tegmental anesthesia area (MPTA), rapidly induces a reversible anesthesia-like state characterized by suppressed locomotion, atonia, anti-nociception and loss of consciousness. GABA-sensitive neurons in the MPTA may therefore have powerful control over major aspects of brain and spinal function. Tracer studies have shown that the MPTA projects to the rostromedial medulla, an important reticulospinal relay for pain modulation and motor control. It also projects directly to the spinal cord. But do individual MPTA neurons project to one or to both targets? We microinjected fluorogold into the rostromedial medulla and cholera toxin b-subunit into the spinal cord, or vice versa. Neurons that were double-labeled, and hence project to both targets, were intermingled with single-labeled neurons within the MPTA, and comprised only 11.5% of the total. MPTA neurons that project directly to the spinal cord were larger, on average, than those projecting to the rostromedial medulla, differed in shape, and were much more likely to express GABAA-alpha1Rs as assessed by receptor alpha-1 subunit immunoreactivity (51.4% vs. 18.9%). Thus, for the most part, separate and morphologically distinct populations of MPTA neurons project to the rostromedial medulla and to the spinal cord. Either or both may be involved in the modulation of nociception and the generation of atonia during the MPTA-induced anesthesia-like state.

Projections from the mesopontine tegmental anesthesia area to regions involved in pain modulation.

Pentobarbital microinjected into a restricted locus in the upper brainstem induces a general anesthesia-like state characterized by atonia, loss of consciousness, and pain suppression as assessed by loss of nocifensive response to noxious stimuli. This locus is the mesopontine tegmental anesthesia area (MPTA). Although anesthetic agents directly influence spinal cord nociceptive processing, antinociception during intracerebral microinjection indicates that they can also act supraspinally. Using neuroanatomical tracing methods we show that the MPTA has multiple descending projections to brainstem and spinal areas associated with pain modulation. Most prominent is a massive projection to the rostromedial medulla, a nodal region for descending pain modulation. Together with the periaqueductal gray (PAG), the MPTA is the major mesopontine input to this region. Less dense projections target the PAG, the locus coeruleus and pericoerulear areas, and dorsal and ventral reticular nuclei of the caudal medulla. The MPTA also has modest direct projections to the trigeminal nuclear complex and to superficial layers of the dorsal horn. Double anterograde and retrograde labeling at the light and electron microscopic levels shows that MPTA neurons with descending projections synapse directly on spinally projecting cells of rostromedial medulla. The prominence of the MPTA's projection to the rostromedial medulla suggests that, like the PAG, it may exert antinociceptive actions via this bulbospinal relay.

Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain.

Abnormal afferent discharge originating at ectopic sites in injured primary sensory neurons is thought to be an important generator of paraesthesias, dysaesthesias, and chronic neuropathic pain. We report here that the ability of these neurons to sustain repetitive discharge depends on intrinsic resonant properties of the cell membrane and that the prevalence of this characteristic increases after nerve injury. Recording from primary sensory neurons in excised rat dorsal root ganglia, we found that some cells show subthreshold oscillations in their membrane potential. The amplitude, frequency, and coherence of these oscillations were voltage sensitive. Oscillations gave rise to action potentials when they reached threshold. Indeed, the presence of oscillations proved to be a necessary condition for sustained spiking both at resting membrane potential and on depolarization; neurons without them were incapable of sustained discharge even on deep depolarization. Previous nerve injury increased the proportion of neurons sampled that had subthreshold oscillations, and hence the proportion that generated ectopic spike discharge. Oscillatory behavior and ectopic spiking were eliminated by [Na(+)](o) substitution or bath application of lidocaine or tetrodotoxin (TTX), under conditions that preserved axonal spike propagation. This suggests that a TTX-sensitive Na(+) conductance contributes to the oscillations. Selective pharmacological suppression of subthreshold oscillations may offer a means of controlling neuropathic paraesthesias and pain without blocking afferent nerve conduction.

Fiber trajectories of olfactory bulb efferents in the hamster.

Olfactory bulb efferents sweep caudally over the surface of the piriform lobe in a broad fiber sheet. The internal organization of this axon population was analysed by topologically transforming the cortical surface from its in situ cylindrical form into an unrolled (flattened) map. The distribution of degeneration elicited by restricted bulb lesions and fiber transections was then reconstructed onto this map. Most of the projection cortex of the main olfactory bulb is innervated in a widespread, non-topographic manner by axons that collect in the compact bundle of the lateral olfactory tract (LOT). LOT collateral branches bound for the prepiriform cortex veer laterally off the main trajectory of the tract at an angle of 50 degrees or less. Thus, transection of discrete fiber populations leaves only a small wedge-shaped pocket of totally denervated cortex distal to the cut. The medial half of the olfactory tubercle and the hippocampal rudiment receive their bulbar input along medially disposed fibers that do not join the LOT proper. The lateral half of the olfactory tubercle, however, receives an input from LOT fiber collaterals as well as these medial bulb efferents. Finally, much of the corticomedial amygdaloid complex receives fibers from the accessory olfactory bulb along a specialized subdivision of the LOT, the accessory olfactory tract. These observations are expressed in a schematic summary of the trajectories of olfactory bulb efferents as they appear in the unrolled map and in the more standard ventral view of the hamster brain.

Neuroplasticity in the rearrangement of olfactory tract fibers after neonatal transection in hamsters.

Olfactory bulb efferent axons run caudally in the lateral olfactory tract (LOT) to end in a broad cortical field in the ventral forebrain. Principles governing the plastic rearrangement of this fiber population after early lesions were probed by cutting the tract in hamster pups and studying the distribution of surviving olfactory bulb projections in adulthood using silver and autoradiographic techniques. The spatial pattern of rearrangement proved to depend on the extent of the cut and also the age at which it was made. For example, after complete LOT section at seven days of age no bulb efferents appeared distal to the cut but the proximal projection increased in laminar thickness and spread laterally and medially beyond its normal cytoarchitectonic boundaries. This spread was less pronounced in animals with earlier or later lesions. After transection of only part of the LOT fibers at seven days of age the proximal input was similarly increased. Just distal to the transection, uncut fibers sprouted collaterals to fill the terminal sites vacated as a result of the lesion. In these cases, however, the farthest distal parts of the projection field lost their normal innervation. In a tentative interpretation of these data it is proposed that developing LOT fibers tend to conserve their total amount of axonal arbor. That is, when distal branches are pruned off surgically, the axon compensates by producing extra proximal branches. When an overabundance of proximal collaterals are produced in axons that have not been surgically pruned the growth of more distal axonal branches is stunted in compensation.

Effect of peripheral nerve injury on receptive fields of cells in the cat spinal cord.

When the sciatic and saphenous nerves are cut and ligated in adult cats, the immediate effect is the production of a completely anesthetic foot and a region in medial lumbar dorsal horn where almost all cells have lost their natural receptive fields (RFs). Beginning at about 1 week and maturing by 4 weeks, some 40% of cells in the medial dorsal horn gain a novel RF on proximal skin, that is, upper and lower leg, thigh, lower back, or perineum. This new RF is supplied by intact proximal nerves and not by sciatic and saphenous nerve fibers that sprouted in the periphery. During the period of switching of RFs from distal to proximal skin there was no gross atrophy of dorsal horn grey matter and no Fink-Heimer stainable degeneration of central arbors and terminals of peripherally axotomized afferents. In intact animals medial dorsal horn cells showed no sign of response to mechanical stimulation of proximal skin. RFs of some of the cells had spontaneous variations in size and sensitivity, but these were not nearly sufficient to explain the large shifts observed after chronic nerve section. Tetanic electrical stimulation of skin or peripheral nerves often caused RFs to shrink, but never to expand. Although natural stimuli of proximal skin would not excite medial dorsal horn cells in intact or acutely deafferented animals, it was found that electrical stimulation of proximal nerves did excite many of these cells, often at short latencies. In the discussion we justify our working hypothesis that the appearance of novel RFs is due to the strengthening or unmasking of normally present but ineffective afferent terminals, rather than to long-distance sprouting of new afferent arbors within the spinal cord.

A normally laminated afferent projection to an abnormally laminated cortex: some olfactory connections in the reeler mouse.

The relative positions of pyramidal and polymorphic cell classes are inverted in the central olfactory cortical structures of the reeler mutant mouse. Each cell class is generated at the normal embryonic time. The polymorphic cells of the mutant, like those of the normal, are generated between E11-E13. The pyramidal cells are formed between E11-E16 in both. Despite the anomalous positions of their somata deep in the cortex the apical dendrites of many pyramidal cells reach and ramify at a superficial cortical level subjacent to the lateral olfactory tract. The main and accessory olfactory bulbs are cytoarchitectonically normal in the mutant and project normally upon the anterior olfactory nucleus, the olfactory tubercle, the hippocampal rudiment, the piriform cortex, the amygdaloid region and the entorhinal cortex. As in the normal animal the axons transverse layer Ialpha, and their terminals are concentrated in the immediately subjacent laminar zone. The rostrally directed cortic-cortical association system of the piriform cortex projects upon the anterior olfactory nucleus in the mutant just as in the normal with a relative concentration of terminals in a lamina subjacent and complementary to the zone of termination afferent systems in the abnormally laminated olfactory cortex of the mutant syggests that, in this system at least, the developmental mechanisms which determine relative position of neuron somata and those which govern axon trajectories and the distribution of axon terminals are largely independent.

Two modes of cutaneous reinnervation following peripheral nerve injury.

The return of sensation to the foot following sciatic nerve crush injury was analyzed behaviorally and electrophysiologically in the rat. Functional recovery begins within four days. Its early phase is accounted for by expansion of the functional distribution of intact neighboring fibers of the saphenous n. It occurs even if the sciatic n. is ligated, and it disappears with section of the saphenous n. Accompanying this functional expansion we began to encounter in electrophysiological recordings from the saphenous n., fibers with unusually large receptive fields (RF's) extending onto the plantar surface of the foot, well beyond their limits in intact rats. All of the expanded RF's were high threshold mechanoreceptors. On about the twentieth day after crushing, the regenerating sciatic n. began to make a functional contribution. This was seen by return of sensation to zones not invaded by the saphenous n. and by the onset of sensation in rats in which the saphenous n. had previously been ligated. With return of the sciatic n. the expanded distribution of the saphenous n. went back to its original boundaries. Correspondingly, we could no longer find expanded saphenous n. RF's. We conclude that cutaneous reinnervation begins with the collateral expansion of high threshold afferents from intact neighboring nerves. This alien innervation is later replaced upon regeneration of the original nerve.

Ephaptic transmission in chronically damaged peripheral nerves.

Several weeks after damage of the sciatic nerve in adult rats, a stable electrical (ephaptic) interaction forms between pairs of injured sensory and motor axons. Fiber-fiber interaction occurs when the nerve ends in a neuroma, after end-to-end nerve suture and after nerve crush injury. Unlike the transient "artificial synapse" created acutely on section of a nerve, this form of crosstalk is long-lasting. Its existence lends support to the hypothesis that ephaptic interaction is an important factor in neurologic pathophysiology.

Heritability of symptoms in an experimental model of neuropathic pain.

Male and female rats underwent transection and ligation of the sciatic and saphenous nerves, and the development of autonomy was monitored. The deafferented animals were then interbred, always selecting males and females that expressed relatively high and, alternatively, relatively low levels of autotomy. Offspring were similarly operated and interbred. By the sixth generation of selective breeding, lines were achieved in which autotomy was consistently high (HA) or consistently low (LA). There was no indication of sex linkage. Thermal and mechanical nocifensive responsiveness co-selected with propensity to express autotomy following nerve injury: response thresholds were lower in HA than in LA rats. F1 hybrids formed by crossing homozygous HA and LA animals showed low levels of autotomy, similar to LA stock. This indicates recessive inheritance of the autotomy trait. Backcrossing F1 hybrids onto the LA line yielded a low autotomy phenotype in almost all cases; backcrossing F1 hybrids onto HA stock yielded about 50% high autotomy and 50% low autotomy. These ratios are consistent with simple mendelian inheritance of a single gene. Taken together, the data suggest that autotomy is inherited as a single-gene autosomal recessive trait.

Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats.

Single units were recorded in dorsal roots or in the sciatic nerve of anaesthetised rats. It was shown by making sections, by stimulation and by collision that some ongoing nerve impulses were originating from the dorsal root ganglia and not from the central or peripheral ends of the axons. In a sample of 2731 intact or acutely sectioned myelinated sensory fibres, 4.75% +/- 3.7% contained impulses generated within the dorsal root ganglia. In 2555 axons sectioned in the periphery 2-109 days before, this percentage rose to 8.6% +/- 4.8%. There was a considerable variation between animals; 0-14% in intact and acutely sectioned nerves and 1-21% in chronically sectioned nerves. The conduction velocity of the active fibres did not differ significantly from the conduction velocity of unselected fibres. The common pattern of ongoing activity from the ganglion was irregular and with a low frequency (about 4 Hz) in contrast to the pattern of impulses originating in a neuroma which usually have a higher frequency with regular intervals. Slight mechanical pressure on the dorsal root ganglion increased the frequency of impulses. Unmyelinated fibres were also found to contain impulses originating in the dorsal root ganglion. In intact or acutely sectioned unmyelinated axons, the percentage of active fibres 4.4% +/- 3.5% was approximately the same as in myelinated fibres but there were no signs of an increase following chronic section. Fine filament dissection of dorsal roots and of peripheral nerves and collision experiments showed that impulses originating in dorsal root ganglia were propagated both orthodromically into the root and antidromically into the peripheral nerve. It was also shown that the same axon could contain two different alternating sites of origin of nerve impulses: one in the neuroma or sensory ending and one in the ganglion. These observations suggest that the dorsal root ganglion with its ongoing activity and mechanical sensitivity could be a source of pain producing impulses and could particularly contribute to pain in those conditions of peripheral nerve damage where pain persists after peripheral anaesthesia or where vertebral manipulation is painful.

Adrenosensitivity of injured afferent neurons does not require the presence of postganglionic sympathetic terminals.

Nerve injury sometimes triggers neuropathic pain states that are exacerbated by sympathetic efferent activity. A classic example is causalgia. The mechanism of coupling between sympathetic efferent activity and the afferent discharge responsible for pain sensation is a subject of controversy. Some authors hold to the 'direct coupling hypothesis' which proposes that noradrenaline (NA), released from sympathetic varicosities, acts directly on alpha-adrenoreceptors located in the membrane of injured primary afferents. Others believe that coupling is indirect; that the effects of NA are mediated by additional, non-adrenergic, chemical substances and their receptors (the 'indirect coupling hypothesis'). For example, it has been proposed that in inflamed skin NA acts back on the sympathetic endings which, secondarily, release a prostanoid mediator which sensitizes afferent endings. We report that the responsiveness of injured afferent axons to systemically applied NA persists, and in fact increases in prevalence, in rats that underwent prior chemical or surgical sympathectomy. The observation of adrenosensitivity in injured afferents in the absence of sympathetic postganglionic endings is consistent with the direct coupling hypothesis, which associates adrenosensitivity with the injured afferent axon. It is not consistent with the indirect coupling hypothesis which requires the presence of sympathetic endings as a source for NA-evoked prostanoid release.

Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa.

(1) When hindlimb peripheral nerves are cut across in rats and mice, there is a tendency for the animal to attack the anaesthetic limb. We have called this attack "autotomy". In this paper we describe the time course and degree of autotomy following various types of nerve injury. (2) Four different types of lesion were applied to the sciatic nerve of rats. The most serious autotomy was produced by section of the nerve and encapsulation of its cut end in a polythene tube. Section followed by immediate resuturing also produced serious autotomy. Simple ligation of the nerve end was followed by less autotomy than encapsulation or cut and resuture. A crush lesion caused only minimal attack. (3) Section of the saphenous branch of the femoral nerve produced no autotomy. However, if the saphenous and sciatic nerves were ligated at the same time so that the entire foot became anaesthetic there was a great increase of autotomy over that seen when the sciatic nerve alone was ligated. This increase with the double lesion occurred even if the saphenous nerve was ligated more than 100 days after the sciatic nerve had been cut. (4) Mice showed autotomy very similar to that seen in rats but the onset was somewhat faster. (5) Reasons are given to propose that autotomy is triggered by an abnormal afferent barrage generated in the cut end of the nerve. Autotomy from peripheral nerve lesions is a different phenomenon from that seen after dorsal root section. Autotomy occurs under conditions which produce anaesthesia dolorosa in man. This simple model may be suitable for studies of the prevention of irritations originating from chronic lesions of peripheral nerves.

Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.

It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.

Heritability of nociception II. 'Types' of nociception revealed by genetic correlation analysis.

Clinical pain syndromes, and experimental assays of nociception, are differentially affected by manipulations such as drug administration and exposure to environmental stress. This suggests that there are different 'types' of pain. We exploited genetic differences among inbred strains of mice in an attempt to define these primary 'types'; that is, to identify the fundamental parameters of pain processing. Eleven randomly-chosen inbred mouse strains were tested for their basal sensitivity on 12 common measures of nociception. These measures provided for a range of different nociceptive dimensions including noxious stimulus modality, location, duration and etiology, among others. Since individual members of inbred strains are identical at all genetic loci, the observation of correlated strain means in any given pair of nociceptive assays is an index of genetic correlation between these assays, and hence an indication of common physiological mediation. Obtained correlation matrices were subjected to multivariate analyses to identify constellations of nociceptive assays with common genetic mediation. This analysis revealed three major clusters of nociception: (1) baseline thermal nociception, (2) spontaneously-emitted responses to chemical stimuli, and (3) baseline mechanical sensitivity and cutaneous hypersensitivity. Many other nociceptive parameters that might a priori have been considered closely related proved to be genetically divergent.

Estrogen replacement therapy and the risk of venous thrombosis.

PURPOSE: Estrogen replacement therapy is believed by many physicians to cause thrombophlebitis and to be contraindicated in women at risk for this disease. However, clinical data supporting this assumption are scant, and further investigation is required. PATIENTS AND METHODS: We tested the estrogen-thrombophlebitis association in a case-control study. Charts of all consecutive women aged 45 years or older with a primary or secondary discharge diagnosis of thrombophlebitis, venous thrombosis, or pulmonary embolism were reviewed; 121 cases and 236 controls matched for age, year of admission, admitting service, and socioeconomic status were obtained. Hormone use and nonuse were validated in a subset of randomly selected women. RESULTS: Cases and controls, whose average age was 65 years, did not differ significantly on matching variables or on current use of exogenous estrogen (5.1% of cases versus 6.3% of controls). Other analyses that variously excluded women with a past history of thrombosis, women less than 50 years of age, women with thrombosis occurring after admission, and women whose estrogen use was indeterminate also did not support an increased risk of thrombotic disease. Adjustment for the presence of independent thrombotic risk factors did not alter the odds ratio for estrogen use. CONCLUSION: This case-control study of older women, unselected for other thrombotic risk factors, does not support the commonly held assumption that replacement estrogen increases the risk of venous thrombosis.

Neurochemical mediators of the behavioural effects of receptor-selective substance P agonists administered intrathecally in the rat.

Recently, two compounds have been developed, designated septide and senktide, which are highly selective agonists for the substance P receptor, types NK-1 and NK-3, respectively. Each of these, when injected intrathecally in awake rats, produced a distinct and non-overlapping constellation of sensory and behavioural effects which were subsets of the symptoms evoked by intrathecal administration of substance P. Prior systemic administration of 5-hydroxytryptamine (5-HT), alpha-adrenergic and opiate receptor antagonists, at doses sufficient to block the behavioural effects of the corresponding receptor agonists, did not alter responses to intrathecally injected septide or senktide. This was so, even for symptoms which suggested inhibitory mediation, hypoalgesia and (transient) motor flaccidity. Septide and senktide, administered by lumbar puncture and by indwelling catheter, produced identical results. Finally, in contrast to some other peptides, flaccid paralysis induced by senktide was not accompanied by spinal necrosis.