PubMed Health⌕ Search

Biomedical subjects

L M Mendell

Publications and source records attributed to L M Mendell.

At least 37 records · Page 2Linked to original sources
PubMed1996

Characteristics of nerve growth factor induced hyperalgesia in adult rats: dependence on enhanced bradykinin-1 receptor activity but not neurokinin-1 receptor activation.

Treatment of adult rats with a single dose of nerve growth factor (NGF, 1 mg/kg, i.p.) results in a prolonged hypersensitivity to noxious thermal stimulation which becomes noticeable within 30 min of administration and lasts for several days. A significant mechanical hyperalgesia develops within 7 h following injection of NGF and persists for up to 7 days. In the present set of experiments we describe certain quantitative features of this hyperalgesia. The initial thermal hyperalgesia can be highly variable and is associated to some degree with the presence of an overt immunologic reaction. The mechanical hyperalgesia is reproducible enough to reveal a clear dependency on the dose of NGF. We also examined the pharmacological properties of the NGF-induced hyperalgesia. The bradykinin BK1 receptor antagonist des-Arg9[Leu8]BK transiently blocked the thermal hyperalgesia when injected 1 day after NGF administration whereas mechanical thresholds were further reduced under this protocol. The BK2 antagonist HOE 140 had no effect on this late NGF-induced hyperalgesia. Injection of the neurokinin NK1 receptor antagonist CP-96345 or its inactive enantiomer CP-96344 one day after NGF both induced a transient block of NGF-induced thermal hyperalgesia indicating a non-specific effect rather than an action at NK1 receptors. This was confirmed by finding no reversal of NGF-induced hyperalgesia by RP67580, another NK1 receptor blocker. These results suggest upregulation and activation of BK1 but not NK1 receptors as an additional, probably peripheral, mechanism for the late phase of NGF-induced thermal hyperalgesia.

Adrenergic beta-Antagonists↗
PubMed1996

Therapeutic neural effects of electrical stimulation.

The use of a functional neuromuscular stimulation (FNS) device can have therapeutic effects that persist when the device is not in use. Clinicians have reported changes in both voluntary and electrically assisted neuromuscular function and improvements in the condition of soft tissue. Motor recovery has been observed in people with incomplete spinal cord injury, stroke, or traumatic brain injury after the use of motor prostheses. Improvement in voluntary dorsiflexion and overall gait pattern has been reported both in the short term (several hours) and permanently. Electrical stimulation of skin over flexor muscles in the upper limb produced substantial reductions for up to 1 h in the severity of spasticity in brain-injured subjects, as measured by the change in torque generation during ramp-and-hold muscle stretch. There was typically an aggravation of the severity of spasticity when surface stimulation reached intensities sufficient to also excite muscle. Animals were trained to alter the size of the H-reflex to obtain a reward. The plasticity that underlies this operantly conditioned H-reflex change includes changes in the spinal cord itself. Comparable changes appear to occur with acquisition of certain motor skills. Current studies are exploring such changes in humans and animals with spinal cord injuries with the goal of using conditioning methods to assess function after injury and to promote and guide recovery of function. A better understanding of the mechanisms of neural plasticity, achieved through human and animal studies, may help us to design and implement FNS systems that have the potential to produce beneficial changes in the subject's central nervous systems.

Animals↗
PubMed1996

Maintenance of modality-specific connections in the spinal cord after neonatal nerve growth factor deprivation.

We have investigated the properties of antidromically identified lamina I neurons in the rat dorsal horn (in vivo) after neonatal administration of antibody to nerve growth factor (anti-NGF). Treatment from postnatal day (P) 2 to P9 yielded normal lamina I cell physiology; most cells responded to mechanical nociception and the remainder had a wide dynamic range (WDR). Extending anti-NGF treatment to P14 reduced the proportion of cells responding to mechanical nociception, increased the proportion of WDR cells, and caused the emergence of cells not driven by cutaneous inputs. Both nociceptive-specific and WDR cells had larger receptive fields, suggestive of enhanced central action of the remaining nociceptive afferents. These findings cannot be explained by direct action of anti-NGF on spinal cord neurons since both P2-9 and P2-14 treatments should have had similar effects given the time course of development of the blood-brain barrier. The results are discussed in terms of previous findings indicating normal numbers of D-hairs and high-threshold mechanoreceptors (HTMRs) after anti-NGF treatment from P2 to P9, but a decline in the number of HTMRs and an increase in the number of D-hairs after treatment from P2 to P14. It is suggested that the reduction in nociceptive neurons and the appearance of neurons not driven by cutaneous stimulation in lamina I results from the reduction in HTMR input. However, D-hair input to lamina I did not increase despite the larger number of these afferents, suggesting that their central action was regulated to maintain appropriate modality relationships between periphery and centre.

Animals↗
PubMed1996

Nerve growth factor NT-5 induce increased thermal sensitivity of cutaneous nociceptors in vitro.

1. Perfusion of the receptive field (RF) of C- or A delta-fiber nociceptors with nerve growth factor (NGF) in an in vitro preparation of the rat saphenous nerve with functionally attached skin induced a significant decrease in heat threshold without changing mechanical or cold sensitivity. 2. NGF-induced thermal sensitization was absent after saline perfusion and in skin taken from mast-cell depleted animals, hence confirming a role for mast cells in NGF-induced thermal hyperalgesia. 3. Neurotrophin-5 (NT-5) also induced a small but significant reduction in heat threshold without affecting mechanical sensitivity. It is speculated that NT-5 exerts its action either directly on the trkA receptor, as with NGF or alternatively through trkB receptors located on sympathetic efferents or on small diameter afferents.

Animals↗
PubMed1996

Maturation in properties of motoneurons and their segmental input in the neonatal rat.

1. The isolated neonatal rat spinal chord preparation was used to investigate the development of segmental afferent input to lumbar motoneourons during the first nine postnatal days. Motoneurons, identified with the use of antidromic stimulation of the ventral roots, were characterized electrophysiologically, and their synaptic input in response to stimulation of the homologous dorsal root was studied. 2. Motoneurons in postnatal day (P) 1-3 preparations exhibited lower rheobase and lower input conductance than those impaled in spinal cords taken from animals at P7-9. This finding is consistent with the increase in motoneuron size known to occur during this time. 3. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked at low-frequency (0.1-Hz) stimulation in high-Ca2+ saline exhibited no change in mean amplitude between P1-3 and P7-9 despite an increase in input conductance of the motoneurons, suggesting that some aspect of these synapses underwent a compensatory change. Polysynaptic EPSPs were smaller in the older animals. 4. When bursts of stimuli were delivered at higher frequencies ranging from 10 to 167 Hz, the EPSPs exhibited substantial depression. The depression of monosynaptic EPSPs was significantly less at P7-9 than at P1-3. Changing the bathing solution from a high-Ca2+ saline to a low-Ca2+/high-Mg2+ saline reduced the amplitude of the monosynaptic EPSP and made it less susceptible to depression during high-frequency stimulation. Facilitation of the evoked response, which has been observed in the adult rat, was never seen under any of these conditions. 5. Although synapses on high-rheobase motoneurons exhibited less depression than those on low-rheobase motoneurons, as anticipated from previous results in adults, the EPSPs at synapses on high-rheobase motoneurons tended to be larger in amplitude, not smaller as expected. This suggests that the specialization among synapses on motoneurons that exists in adults has not yet developed by P7-9. Instead, EPSP amplitude may be greater in motoneurons that have been growing rapidly, such as the high-rheobase motoneurons found during these stages of development. 6. Evidence is presented that the growing diversity shown in modulation behavior at the Ia afferent motoneuron synapse during the first postnatal week is determined primarily by motoneuron characteristics. It is speculated that as motoneurons grow during the immediate postnatal period, the presynaptic terminal regions of axons terminating on them become specialized to render the synapse less susceptible to depression. This specialization may be myelination of the afferent terminals or may perhaps be related to the transmitter release process itself. The adult distribution of depression develops later, presumably as the components of the monosynaptic reflex mature.

Afferent Pathways↗
PubMed1995

Rescue of motoneuron and muscle afferent function in cats by regeneration into skin. I. Properties of afferents.

1. In this study we investigate the peripheral receptive field properties and spinal cord connections of low-threshold muscle afferent fibers cross-regenerated into the skin to determine whether a cutaneous target can rescue physiological functions lost after chronic axotomy. 2. In adult cats the medial gastrocnemius (MG) muscle nerve was coated with the distal cut end of either the caudal or lateral cutaneous sural nerves and allowed to regenerate into the hairy skin (postoperative period 6-30 mo). During terminal acute experiments we made recordings of single MG afferent fibers in dorsal root filaments and peripheral nerve. Conduction velocity and receptive field characteristics were determined for each fiber. In addition, the MG nerve was stimulated to elicit cord dorsum potentials and monosynaptic excitatory postsynaptic potentials (EPSPs) in heteronymous motoneurons. As controls, studies were carried out after MG nerve axotomy (postoperative period 2.5-12 mo). 3. After innervation of the skin, MG muscle afferent fibers exhibited firing characteristics and proximal segment conduction velocities like those of normal MG afferents. Responses to skin and hair stimulation consisted primarily of slowly adapting, stretch-sensitive, and steady discharge patterns, all common in normal muscle afferents but not in cutaneous afferents. These properties were observed despite the innervation of touch domes and single hairs, suggesting that the peripheral physiology of muscle afferents is a function of the axonal membrane and is not respecified by a cutaneous target and/or receptors. 4. Cord dorsum potentials were characteristic of those elicited by intact muscle afferents rather than skin afferents and showed recovery of configurations lost after chronic axotomy. 5. The monosynaptic EPSPs elicited in lateral gastrocnemius-soleus motoneurons also recovered from the reduction in amplitude observed after chronic axotomy. The configurations of these EPSPs were characteristic of muscle afferents rather than skin afferents. 6. These experiments demonstrate that the peripheral and central physiological properties of muscle afferents are rescued from the axotomy state if the afferents are allowed to reinnervate skin. We found no evidence that respecification had occurred to bring the function of muscle afferents into accord with the new cutaneous target.

Animals↗
PubMed1995

Rescue of motoneuron and muscle afferent function in cats by regeneration into skin. II. Ia-motoneuron synapse.

1. In this study we describe application of high-frequency stimulation to the group Ia afferent-to-motoneuron synapse of cats to determine the extent to which regeneration of axotomized muscle afferents and motoneurons into skin or into muscle rescues their ability to generate excitatory postsynaptic potentials (EPSPs). 2. The medial gastrocnemius (MG) muscle nerve was transected and 1) left chronically axotomized, 2) cross-united to the caudal cutaneous sural (CCS) nerve, or 3) self-united. The ability of the operated MG muscle afferents to generate EPSPs in normal lateral gastrocnemius-soleus (LGS) motoneurons and of normal LGS muscle afferents to generate EPSPs in the operated MG motoneurons was tested 5 wk-30 mo later. 3. EPSPs were generated by bursts of 32 shocks at 167 Hz and averaged in register. In normal cats, EPSP amplitude decreased (negative modulation) during these bursts in type S motoneurons and could increase or decrease in type F motoneurons (positive or negative modulation). 4. After axotomy, EPSPs generated both in axotomized motoneurons and by axotomized afferents showed only negative modulation during the burst, and the negative modulation was much greater than in normal animals. Regeneration of the muscle nerve into skin significantly decreased the negative modulation relative to axotomy. Regeneration of the muscle nerve into muscle restored the EPSP modulation behaviors even more, to essentially normal values. 5. We conclude that the ability of muscle afferents to generate EPSPs in motoneurons in response to high-frequency stimulation, and the ability of motoneurons to express those EPSPs, are both influenced by the target innervated by those neurons. Synaptic efficacy is severely reduced by target deprivation (axotomy), partially rescued by cross-regeneration into skin, and rescued virtually completely by regeneration into the native muscle. We speculate on the role of target-derived neurotrophins in these effects.

Animals↗
PubMed1995

Properties of regenerated primary afferents and their functional connections.

1. The tibial and sural nerves in cats were cut, anastomosed to their distal stumps, and allowed to regenerate for 3-17.5 mo. In the terminal acute experiment, individual afferents were impaled in the dorsal root ganglion to study their receptive field properties, somatic spike parameters, and spinal projections using cord dorsum potential (CDP) measurements. Properties of the CDPs provided evidence on whether the afferent fibers were originally proprioceptive or cutaneous (rapidly or slowly adapting). 2. Fibers with the largest conduction velocity were selectively slowly adapting, suggesting that large muscle afferents maintained their adaptation properties regardless of the peripheral structure innervated. Similarly, the relationship of somatic spike configuration to mechanical threshold was largely normal. Cells with narrow spikes innervated low-threshold mechanoreceptors, whereas cells with broad spikes and an inflection on the descending limb innervated high-threshold mechanoreceptors. 3. Spikes with intermediate properties were observed in some cells that innervated low-threshold mechanoreceptors in the periphery. These were classified as "hybrid" spikes. 4. The largest CDPs were evoked by afferents classified as having originally been cutaneous fibers, regardless of whether they had reinnervated cutaneous or subcutaneous receptors. Fibers classified as has having originally been proprioceptive afferents produced much smaller CDPs; however, these afferents never produce CDPs in intact preparations. Afferents nonresponsive to peripheral stimulation, classified putatively as having been cutaneous, also evoked small CDPs. 5. Fibers classified as putatively cutaneous or proprioceptive could reinnervate foreign target tissue (subcutaneous tissue or skin, respectively), but a propensity to reinnervate the original target tissue was observed. 6. Among putative cutaneous afferents, those with rostrocaudal CDP distributions somatotopically correct for the location of their receptive fields evoked the largest CDPs regardless of the peripheral tissue innervated. 7. We conclude that receptive field properties (adaptation, mechanical threshold) of regenerated afferents are well matched with the electrophysiological properties of the soma and axon. The properties of the central projections of these afferents are not as well matched with their peripheral receptor properties. This is discussed in terms of the plasticity of the central projections of axotomized afferents.

Action Potentials↗
PubMed1994

Peripheral and central mechanisms of NGF-induced hyperalgesia.

Mechanisms underlying the hyperalgesia induced by a single systemic injection of nerve growth factor (NGF) in adult rats were studied in vivo. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals which had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5-hydroxytryptamine receptor antagonists (ICS 205-930 and methiothepin) also developed an NGF-induced thermal hyperalgesia, but onset was delayed by more than 3 h. In the presence of ICS 205-930 or methiothepin the early component NGF-induced hyperalgesia was reversed and the animals responded with an initial hypoalgesia to the thermal stimuli. Whereas these results indicate a peripheral mechanism for the initial thermal hyperalgesia, the later phase (7 h-4 days after NGF) appeared to be centrally maintained, since it could be selectively blocked by the non-competitive NMDA receptor antagonist MK-801. In contrast to the almost immediate thermal hyperalgesia following a single injection of NGF, a significant mechanical hyperalgesia began only after a 7 h latency. This NGF-induced mechanical hyperalgesia was not blocked by any of the treatments that attenuated the thermal hyperalgesia, indicating that a separate mechanism may be involved. Additional electrophysiological experiments showed that NGF-induced hyperalgesia was not maintained by an increased amount of spontaneous activity in C-fibres. A final result showed that endogenous release of NGF in a model of acute inflammation (complete Freund's adjuvant-induced inflammation) may be involved in the development of thermal hyperalgesia, since it could be blocked by concomitant treatment with anti-NGF antisera. These data indicate that NGF-induced thermal and mechanical hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism involving the degranulation of mast cells, whereas the late component involves central NMDA receptors. In contrast, the NGF-induced mechanical hyperalgesia seems to be independent of mast cell degranulation or central NMDA receptor sites.

Animals↗
PubMed1994

Retrograde determination of motoneuron properties and their synaptic input.

Both motoneurons and the muscle fibers that they innervate can vary widely in their properties. The finding that these properties are highly correlated indicates that these cells are not specified independently, but rather interact in some manner to achieve the observed coherence. The direction of the interaction, i.e., whether orthograde or retrograde, requires analysis beyond the simple observation of these correlated properties. Evidence, largely from experiments involving reinnervation of muscle by the original or a foreign motor nerve, suggests the action of retrogradely transported factors from the muscle as well as orthograde ones. Various possible factors, specifically neurotrophins, are advanced as possible candidates for retrograde specification. In addition, synaptic input to motoneurons also varies in a coordinated fashion in a manner that suggests a retrograde determination from the muscle. However, motoneuron properties and their synaptic input change after peripheral nerve manipulations such that they are no longer in register. This indicates some independence in retrograde specification of motoneurons and their synaptic input.

Animals↗
PubMed1994

Regulation of cutaneous C-fiber heat nociceptors by nerve growth factor in the developing rat.

1. Previous work has indicated that nerve growth factor (NGF) is an important factor for the development of nociceptive A-delta fibers. Here we asked if the availability of NGF during the first 2 wk of development can influence the phenotypic development of unmyelinated afferent C-fibers. 2. To do this, we treated newborn rats with antibodies to NGF from postnatal day (PND) 2-14, a treatment known not to lead to cell death, or with exogenous NGF (PND 0-14). Untreated litter mates served as controls. When the animals were mature (5-20 wk later), they were anesthetized (urethan, 1.25 g/kg ip) and single-unit recordings were made from sural nerve C-fibers in dorsal root filaments. To obtain an unbiased estimate of the physiological types present, an electrocutaneous search technique was employed to isolate the location of the putative receptive field of the C-fiber being studied within the sural nerve territory. This technique enabled us to acquire a sample of C-fibers that was unbiased by natural search stimuli which are often damaging to skin. 3. We found that the proportion of C-fibers that could be driven by noxious heat and mechanical stimuli (C-mechanoheat fibers, C-MH) was reduced from 28% (11/40 fibers) of the sample in controls to 10% (3/31 fibers) in anti-NGF treated animals. The C-MH fibers appeared to have been replaced by a novel type of pressure receptor with an unusually low mechanical threshold (mean 0.86 +/- 0.58 compared with 13.0 +/- 8.3 g for control mechanonociceptors).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Central sprouting and functional plasticity of regenerated primary afferents.

A combination of neuroanatomical and electrophysiological techniques was used to study the effects of peripheral axotomy and regeneration of primary afferents on their central projections in the spinal cord. Individual regenerated afferent fibers were impaled with HRP-filled electrodes in the dorsal columns of alpha-chloralose-anesthetized cats and activated by current pulses delivered via the intracellular electrode. The resulting cord dorsum potentials (CDPs) were recorded at four rostrocaudal locations and HRP was iontophoretically injected into the fiber. Central distributions of boutons and CDPs were compared with peripheral receptor type to determine the accuracy of peripheral regeneration and the effects of central-peripheral mismatches. Reconstruction of the central projections of 13 individual afferents for which the adequate stimulus and CDPs had been recorded revealed many abnormalities. For example, unlike controls, four group I and II afferents with central projections typical of proprioceptors (concentrated in laminae V, VI, and VII) innervating either cutaneous or noncutaneous targets evoked measurable CDPs. Three other group II or A beta afferents innervating low-threshold mechanoreceptors with central terminations confined to the dorsal horn exhibited extensive collateralization in laminae I and II in addition to large numbers of terminals in laminae III-IV. These fibers activated central networks whose adaptation behavior was identical to those evoked by high-threshold mechanoreceptive afferents in controls. These results suggest that primary afferents and their central connections are capable of significant modifications following axotomy and regeneration. In addition, the anatomical studies indicate some reorganization in the laminar distribution of boutons as well as in bouton size.

Afferent Pathways↗
PubMed1993

Nerve growth factor and nociception.

Nerve growth factor (NGF) is thought of as a target-derived factor responsible for the survival and maintaining the phenotype of specific sets of peripheral and central neurons during development and maturation. Recently, using physiological techniques, we have shown that specific functional types of nociceptive sensory neurons require NGF, first for survival during development in utero and then for their normal phenotypic development (but not survival) in the early postnatal period. In adulthood, the physiological role of NGF changes dramatically and here it may serve as a link between inflammation and hyperalgesia. Despite apparent changes in NGF's mode of action as the animal matures, it always interacts specifically with nociceptive sensory neurons.

Animals↗
PubMed1993

Altered expression of nerve growth factor in the skin of transgenic mice leads to changes in response to mechanical stimuli.

It has recently become clear that the neurotrophic factor, nerve growth factor, interacts specifically with nociceptive sensory neurons during development and maturity. Indeed, it may serve as a critical link between inflammation and the hyperalgesia that ensues in adult animals. Nerve growth factor is normally expressed in limiting amounts in target tissues of sensory and postganglionic sympathetic neurons. In the present study we have altered the basal level of nerve growth factor expression in the skin by producing transgenic mice that express a fusion gene construct containing either a sense or antisense nerve growth factor complementary DNA linked to the K14 keratin promoter. The K14-nerve growth factor transgene (sense or antisense) is abundantly expressed in skin from approximately embryonic day 15 and is then constitutively expressed throughout the life of the animal. In light of the fact that systemic administration of nerve growth factor to neonatal or adult rats leads to hyperalgesia, we have asked whether mice expressing the sense K14-nerve growth factor transgene exhibit similar sensory abnormalities and whether mice expressing the antisense nerve growth factor complementary DNA were hypoalgesic. Here we show that mice over-expressing nerve growth factor in skin display a profound hyperalgesia to noxious mechanical stimulation. Additionally, K14-nerve growth factor antisense mice displayed a profound hypoalgesia to the same stimuli.

Animals↗
PubMed1993

Regulation of myelinated nociceptor function by nerve growth factor in neonatal and adult rats.

The role of nerve growth factor (NGF) as a survival factor for sensory neurons during embryonic life has been well documented. Here we examine the actions of NGF or antisera against NGF (anti-NGF) on physiologically identified sensory neurons with myelinated axons later in life, after the dependence on NGF for survival ends. We find that the effects of NGF and anti-NGF are specific for sensory neurons which are nociceptors. Treatments were found to affect the biophysical properties, the development, or the physiological function of myelinated nociceptors. They also affect the animal's behavioral response to noxious stimulation, depending upon when the treatments were given: neonatally, from 2-5 weeks of age, or chronically, beginning at birth. Thus, we find that the actions of NGF are specific for nociceptors but that the function of this neurotrophic factor changes according to the developmental age of the animal.

Animals↗
PubMed1993

Quantitative ultrastructure of Ia boutons in the ventral horn: scaling and positional relationships.

Three physiologically characterized spindle (group Ia) afferents were labeled by the intracellular injection of HRP and were processed for light-level reconstruction. Thirty-five boutons in the ventral horn were then selected for analysis. They were serially thin sectioned and characterized in terms of volume, total surface area and the surface area of apposition to postsynaptic neurons (apposed surface area), mitochondrial volume, vesicle and active zone features, relation to presynaptic contacts, postsynaptic profile size, and position within the terminal arbor. Virtually all of these characteristics were widely variable, both within the entire population and in the endings of a single fiber. Apposed surface area, mitochondrial volume, vesicle number, active zone vesicle number, active zone number, and total active zone area were highly correlated in a positive linear manner with bouton volume. This suggests a type of ultrastructural "size principle," in which the morphological features associated with synaptic release scale directly in proportion to bouton size. This pattern also extends to local circuit interactions: the extent of an Ia bouton's input from axoaxonal contacts (86% receive at least one axoaxonal contact) was directly proportional to its size. In addition, the characteristics of an Ia bouton were related to its position on the postsynaptic element and within the terminal arbor. Vesicle density, percentage mitochondrial volume, and active zone size increased as the postsynaptic process decreased in size, while volume, apposed surface area, active zone number and area, and vesicle number all decreased as one moved downstream within a terminal branch, with the exception of the terminal bouton. Vesicle density also decreased as one moved away from the dorsal root entry zone.

Afferent Pathways↗
PubMed1993

Nerve growth factor-induced hyperalgesia in the neonatal and adult rat.

Recently, we have shown that the interaction between NGF and sensory neurons in early postnatal periods is restricted to nociceptive afferents (Ritter et al., 1991; Lewin et al., 1992a; Ritter and Mendell, 1992). Here we show that administration of excess NGF to neonatal or mature animals can lead to a profound behavioral hyperalgesia. Neonatal NGF treatment (postnatal day 0-14) resulted in a profound mechanical hyperalgesia that persisted until the animals had reached maturity (6 weeks of age). This hyperalgesia could be explained by an NGF-mediated sensitization of A delta nociceptive afferents to mechanical stimuli. This peripheral sensitization wore off with a time course similar to that of the behavior hyperalgesia. Treatment of animals from the second postnatal week until 5 weeks of age (juveniles) led to a very similar behavioral hyperalgesia; however, there was no corresponding sensitization of A delta nociceptors to mechanical stimuli. Finally, one group of adult animals (5 weeks old) was treated daily with single injections of NGF for between 1 and 4 d. Within 24 hr after the first NGF injection these animals developed a mechanical hyperalgesia of the same magnitude seen after neonatal and juvenile NGF treatments. No sensitization of A delta nociceptive afferents was observed in these animals. In addition to the mechanical hyperalgesia, the animals also developed a heat hyperalgesia after one injection of NGF. The heat hyperalgesia was apparent within 15 min after the injection; however, signs of mechanical hyperalgesia were not seen until 6 hr after the injection. In conclusion, it appears that the NGF-induced mechanical hyperalgesia is brought about by different mechanisms in neonatal and adult rats. Furthermore, in adult animals the NGF-induced mechanical and heat hyperalgesia also appear to be attributable to two different mechanisms. The mechanical hyperalgesia may be due to central changes (see Lewin et al., 1992b), whereas the heat hyperalgesia is likely to result at least in part from the sensitization of peripheral receptors to heat.

Aging↗