C-fiber mechanical stimulus-response functions are different in inflammatory versus neuropathic hyperalgesia in the rat

To compare changes in primary afferent nociceptors associated with inflammatory versus neuropathic hyperalgesia, we evaluated in rats the mechanical stimulus-response function of isolated C-fiber primary afferent nociceptors to 10-s stimuli of differing mechanical strengths; 36 fibers after prostaglandin E2, 28 fibers from streptozotocin-diabetic rats and 46 fibers from control, non-treated rats were examined. Intradermal injection of prostaglandin E2 decreased mechanical threshold of 19 of 35 (54%) C-fibers. C-fibers that demonstrated a decrease in the mechanical threshold after prostaglandin E2 also showed an increased response to suprathreshold stimuli. The increase in the number of action potentials in prostaglandin E2-treated C-fibers was greatest at lower magnitude stimulus intensities, i.e. near threshold; the response to higher magnitude stimulus intensities was unchanged from that in control animals. In contrast, an increase in the number of action potentials seen in C-fibers from streptozotocin-diabetic rats was not seen at low-magnitude stimulus intensities; rather, a pronounced increase in response was seen at high-magnitude stimulus intensities. The von Frey hair thresholds for C-fibers in streptozotocin-diabetic rats were not different from those in control C-fibers. These data suggest that the changes in mechanical stimulus-response function of C-fibers are different in inflammatory compared to neuropathic mechanical hyperalgesia. These differences may underlie some of the differences in clinical features between inflammatory and neuropathic hyperalgesias.     

Bone mass and structure at the hip in men and women over the age of 60 years

To examine the effects of nerve growth factor (NGF) on the response to bradykinin (BK) of primary afferent neurons, intracellular recordings were obtained from small (< 30 microm) and large (> or = 35 microm) neurons in rat dorsal root ganglia (DRG). The response to BK in the small neurons was tested in 23 freshly dissociated neurons (dissociated group), 37 neurons cultured in the absence of NGF (no-NGF group) and 117 neurons in the presence of NGF (NGF group). Application of BK (10(-7) or 10(-5) M) induced a depolarization in a small number of neurons in the freshly dissociated (13%) and the no-NGF (11%) groups. After cultivation with NGF, the percentage of neurons that were depolarized by BK significantly increased to 46% after 2 days of cultivation. In the NGF group, the percentage of neurons sensitive to BK was significantly greater among capsaicin (CAP)-sensitive than among CAP-insensitive neurons (48 vs 20%). This BK-induced depolarization was completely blocked by a B2 receptor antagonist, but not a B1 receptor antagonist. With large neurons, in contrast, NGF did not increase the percentage that were BK-sensitive (9% in the dissociated group vs 0% after being cultured 2 days with NGF). These results demonstrate that NGF increases sensitivity to BK, mediated through B2 receptors only, in capsaicin-sensitive small neurons cultured from rat DRGs.     

Nerve growth factor receptor-like immunoreactivity in the human spinal cord

Nerve growth factor (NGF) receptor-like immunoreactivity has been demonstrated in the normal human adult spinal cord using the monoclonal antibody ME20.4. Intense immunoreactivity was associated with fibres and terminals in the substantia gelatinosa. In lamina IX the neuropil demonstrated punctate staining, the motor neurons themselves being negative. At thoracic levels occasional neurons of the intermediolateral column cell group were NGF receptor positive. Fine axonal and punctate terminal reactivity was observed in the gracile fasciculus, corresponding to axons in transverse section. Similar, though slightly less dense immunoreactivity was observed in the cuneate fasciculus. The demonstration of NGF receptor immunoreactivity may provide a useful marker of sensory innervation in the human spinal cord.     

Mechanical response properties of nociceptors innervating feline hairy skin

1. The responses of feline cutaneous nociceptors were examined in vivo by systematically manipulating the intensive and spatial dimensions of mechanical stimulation. A computer-controlled motor was used to apply prescribed forces (5-90 g) to a nociceptor's receptive field, with flat-tipped, cylindrical probes of various sizes (contact areas: 0.1-5.0 mm2). The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing for comparisons of the two data sets. 2. With a ramp-and-hold stimulus of controlled force, most nociceptors showed a slowly adapting (SA) response throughout the stimulus. In this way, nociceptors resembled low-threshold SA mechanoreceptors. However, in contrast to SA mechanoreceptors, nociceptors failed to exhibit an onset burst of activity associated with the stimulus ramp. Nineteen percent (6 of 31) of the nociceptors often showed the opposite trend during the stimulus, e.g., a gradually increasing firing rate. Most of these nociceptors (5 of 6) had particularly high mechanical thresholds. 3. With 30 stimuli repeated at short intervals (6-8 s), response rates tended to decrease across trials. This phenomenon was most evident with more intense stimuli. When two series of stimuli were separated by 4-5 min, there was no apparent trend of reduced responsiveness between series. 4. Overall, nociceptors responded in an orderly way to variations in force and probe size. For a given probe size, larger forces produced greater responses; for a given force, smaller probes produced greater responses. The relationship between probe size and force was best described as an even tradeoff between force and a linear dimension of the probe (i.e., probe perimeter), rather than the area of the probe. Thus a given pressure (force/area) did not evoke the same response from nociceptors as probe size was varied. 5. There were two significant differences in the mechanical responsiveness between A fiber and C fiber nociceptors. First, for a given set of stimuli, A fiber nociceptors exhibited a greater response rate than the C fiber nociceptors. Second, the A fiber nociceptors exhibited a greater differential response related to probe size than the C fiber nociceptors. On the basis of these two features, the A fiber nociceptors' response profiles showed a closer parallel with previously reported human pain thresholds than the C fiber nociceptors did. 6. When the nociceptors were subdivided as to their mechanical threshold, those with lower thresholds [mechanically sensitive afferents (MSAs)] showed a response saturation with the more intense stimuli. On average, the stimulus levels at which saturation occurred were close to human pain threshold. Those nociceptors with higher thresholds [mechanically insensitive afferents (MIAs)] did not show such saturation. Thus only the MIAs appeared to have the capacity to unambiguously encode mechanical stimulus intensities above pain threshold. The MSAs, on the other hand, exhibited their greatest dynamic response range near the threshold for nonpainful sharpness. Thus the group of afferents commonly defined as nociceptors exhibit a heterogeneity of mechanical response properties, which may serve functionally different roles for perception.     

Sensitization of C-fibres by prostaglandin E2 in the rat is inhibited by guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor peptide

Behavioral studies have shown that mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 is blocked by inhibitors of the cAMP second messenger system. Similarly, injection of prostaglandin E2 also induces a decrease in mechanical threshold and an increase in the number of action potentials elicited by test stimuli in most C-fibre nociceptors. This change is called sensitization. To further evaluate the degree of correlation between primary afferent sensitization and mechanical hyperalgesia, we conducted a study to evaluate the effect of agents known to block the cAMP second messenger system and behavioral manifestations of mechanical hyperalgesia following injection of prostaglandin E2. The agents tested were guanosine 5'-O-(2-thiodiphosphate), an inhibitor of stimulatory guanine nucleotide-binding regulatory proteins; 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase; and Walsh Inhibitor Peptide, an inhibitor of cAMP-dependent protein kinase. Single fibre electrophysiologic studies of 138 C-fibres, innervating the dorsum of the hind paw, was done in male Sprague-Dawley rats. The number of spikes evoked by a 10 s application of a threshold von Frey hair were determined before and after intradermal injection of test agents administered alone and in combination with prostaglandin E2. Injection of prostaglandin E2 with the test agent vehicle (saline or distilled water) resulted in a significant decrease in von Frey hair threshold and an increase in the number of spikes generated in response to threshold von Frey hairs. In contrast, co-injection of prostaglandin E2 with guanosine-5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine or Walsh inhibitor peptide did not result in a significant decrease in von Frey hair mechanical threshold or increase in the number of spikes generated to the threshold stimuli, compared with vehicle/prostaglandin E2. It is suggested that guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor protein inhibited prostaglandin E2 sensitization of primary afferent C-fibres by inhibiting a stimulatory guanine nucleotide-binding regulatory protein, adenylyl cyclase, and protein kinase A, respectively. These results support the hypothesis that primary afferent sensitization by prostaglandin E2 underlies prostaglandin E2-induced hyperalgesia.     

Primary afferent tachykinins are required to experience moderate to intense pain

The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation. Because blockers of glutamate receptors reliably reduce pain behaviour, it is assumed that 'pain' messages are mediated by glutamate action on dorsal horn neurons. The contribution of substance P, however, is still unclear. We have now disrupted the mouse preprotachykinin A gene (PPT-A), which encodes substance P and a related tachykinin, neurokinin A. We find that although the behavioural response to mildly painful stimuli is intact in these mice, the response to moderate to intense pain is significantly reduced. Neurogenic inflammation, which results from peripheral release of substance P and neurokinin A, is almost absent in the mutant mice. We conclude that the release of tachykinins from primary afferent pain-sensing receptors (nociceptors) is required to produce moderate to intense pain.     

Chemosensitivity of nociceptive, mechanosensitive afferent nerve fibres in the guinea-pig ureter

The mechanosensitivity and chemosensitivity of afferent fibres were investigated in an in vitro preparation of the guinea-pig ureter. Electrophysiological recordings were obtained from 5 U-1 (low mechanical threshold, contraction-sensitive) and 74 U-2 units (high threshold). U-2 units had significant higher levels of spontaneous activity, lower conduction velocities, higher mechanical thresholds (U-1: 7 mmHg; U-2: 39 mmHg), less pronounced phasic responses and longer latencies in the response to distensions than the U-1 units. For chemical stimulation, guinea-pig urine (> 800 mosmol/L), bradykinin and capsaicin were applied intraluminally. The responses of U-1 units mainly corresponded to the contractions induced by the chemical stimulation. The vast majority of the U-2 units were excited by urine, bradykinin (threshold: 0.1-1 microM) and capsaicin (threshold: 0.03-0.3 microM). The responses to urine could be mimicked by high concentrations of potassium ions (> 200 mM), but not by an equiosmolar solution of NaCl, urea and mannitol. Chemical stimulation could also result in a transient sensitization of the U-2 units to mechanical stimuli. In the anaesthetized guinea-pig, pseudo-affective responses could be evoked by ureteric distension (threshold: 30-60 mmHg) and serosal application of capsaicin. Intraluminal application of urine in vivo did not evoke any reactions, suggesting that the responses of the U-2 units to urine might be due to an impaired barrier function of the urothelium in vitro. The data are in agreement with the hypothesis that U-2 units are visceral polymodal nociceptors. Since the U-1 units were also able to encode at least noxious mechanical stimuli, their involvement in visceral nociception cannot be excluded.     

Receptive properties of mouse sensory neurons innervating hairy skin

Using an in vitro nerve skin preparation and controlled mechanical or thermal stimuli, we analyzed the receptive properties of 277 mechanosensitive single primary afferents with myelinated (n = 251) or unmyelinated (n = 26) axons innervating the hairy skin in adult or 2-wk-old mice. Afferents were recorded from small filaments of either sural or saphenous nerves in an outbred mice strain or in the inbred Balb/c strain. On the basis of their receptive properties and conduction velocity, several receptor types could be distinguished. In adult animals (>6 wk old), 54% of the large myelinated fibers (Abeta, n = 83) showed rapidly adapting (RA) discharges to constant force stimuli and probably innervated hair follicles, whereas 46% displayed a slowly adapting (SA) response and probably innervated Merkel cells in touch domes. Among thin myelinated fibers (Adelta, n = 91), 34% were sensitive D hair receptors and 66% were high-threshold mechanoreceptors (AM fibers). Unmyelinated fibers had high mechanical thresholds and nociceptive functions. All receptor types had characteristic stimulus-response functions to suprathreshold force stimuli. Noxious heat stimuli (15-s ramp from 32 to 47 degrees C measured at the corium side of the skin) excited 26% (5 of 19) of AM fibers with a threshold of 42.5 +/- 1.4 degrees C (mean +/- SE) and an average discharge of 15.8 +/- 9.7 action potentials and 41% (7 of 17) C fibers with a mean threshold of 37.6 +/- 1.9 degrees C and an average discharge of 22.0 +/- 6.0 action potentials. Noxious cold stimuli activated 1 of 10 AM fibers and 3 of 10 C fibers. One of 10 C units responded to both heat and cold stimuli. All types of afferent fibers present in adult mice could readily be recognized in mice at postnatal day 14. However, fibers had reduced conduction velocities and the stimulus-response function to mechanical stimuli was more shallow in all fibers except for the D hairs. In juvenile mice, 22% of RA units also displayed an SA response at high stimulus intensities; these units were termed RA/SA units. We conclude that all types of cutaneous afferent fibers are already committed to their phenotype 2 wk after birth but undergo some maturation over the following weeks. This preparation has great potential for the study of transgenic mice with targeted mutations of genes that code factors that are involved in the specification of sensory neuron phenotypes.     

Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties

To compare the heat responses of mechanically sensitive and mechanically insensitive A-fiber nociceptors, an electrical search technique was used to locate the receptive fields of 156 A-fibers that innervated the hairy skin in the anesthetized monkey (77 A beta-fibers, 79 A delta-fibers). Two-thirds of these afferents were either low-threshold mechanoreceptors (n = 91) or low-threshold cold receptors (n = 11). Nine A beta-fibers and 41 A delta-fibers were cutaneous nociceptors, and four A delta-fibers innervated subcutaneous tissue. The majority of cutaneous A-fiber nociceptors were heat sensitive (43/50 = 86%). Heat-insensitive cutaneous A-fiber nociceptors consisted of one cold nociceptor, three silent nociceptors, and three high-threshold mechanoreceptors. Two types of response were observed to an intense heat stimulus (53 degrees C, 30 s). Type I (n = 26) was characterized by a long latency (mean: 5 s) and a late peak discharge (16 s). Type II (n = 17) was characterized by a short latency (0.2 s) and an early peak discharge (0.5 s). Type I fibers exhibited faster conduction velocities (25 vs. 14 m/s) and higher heat thresholds (> 53 vs. 47 degrees C, 1-s duration) than type II fibers. The possibility that the type I heat response was a result of sensitization was tested in three fibers by determining the heat threshold to 30-s duration stimuli (42-46 degrees C). For this long stimulus duration heat thresholds were reproducible across multiple runs, and the threshold to the 1-s duration stimulus was not altered by these tests. Thus fibers with a type I heat response were not high-threshold mechanoreceptors that developed a heat response through sensitization. Fibers with a type II heat response had significantly higher mechanical thresholds (median: 15 bar) than fibers with a type I heat response (5 bar). This finding accounts for the observation that type II heat responses were infrequently observed in earlier studies wherein the search technique depended on mechanical responsiveness. Fibers with a type II response exhibited a graded response to heat stimuli, marked fatigue to repeated applications of heat stimuli, and adaptation to sustained heat stimuli similar to that seen in C-fiber nociceptors. First pain sensation to heat is served by type II A-fiber nociceptors that are mechanically insensitive. Type I A-fiber nociceptors likely signal pain to long-duration heat stimuli and may signal first pain sensation to mechanical stimuli.     

Unmyelinated innervation of sinus hair follicles in rats

Unmyelinated nerve fibres comprise approximately one third of the innervation of rodent sinus hair follicles but their function is unknown. They may play a role as high-threshold sensory fibres, or may be autonomic efferents controlling the vascular sinus. In the present experiments capsaicin and surgical sympathectomy were used to establish whether these unmyelinated fibres are afferent fibres or autonomic efferents. The deep vibrissal nerves of mystacial follicles (C1 and C4) and a non-mystacial follicle (the postero-orbital, PO) were assessed in normal adult animals (n = 6) and compared with those treated with neonatal capsaicin (n = 6) or bilateral superior cervical ganglionectomy (n = 7). In capsaicin-treated animals, counts of fibres in the deep vibrissal nerves from all follicles showed normal numbers of myelinated axons, but approximately 80% reduction in unmyelinated fibres (normal mean +/- SD: C1 94 +/- 10, C4 89 +/- 9, PO 85 +/- 6; after neonatal capsaicin: C1 17 +/- 8, C4 16 +/- 6, PO 18 +/- 6; n = 6, P < 0.001 for all follicles). After sympathectomy there was no significant reduction in myelinated or unmyelinated fibre numbers. Labelling of PO follicles with WGA-HRP showed minimal numbers of labelled cells (0-10) within the superior cervical ganglion, also suggesting minimal sympathetic innervation. This sparse sympathetic supply to the follicle was further demonstrated by a lack of tyrosine hydroxylase reactivity within the follicle complex; tissues outside the dermal capsule showed reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrafamilial clustering and 4-year follow-up of asymptomatic human T-cell leukaemia virus type I (HTLV-I) infection in Benin (West Africa)

Most primary sensory neurones depend on neurotrophins for survival. Mutant mice in which TrkA, the high-affinity receptor for nerve growth factor (NGF), has been inactivated lack nociceptive neurones in sensory ganglia and do not respond to noxious stimuli. The cornea of the eye is innervated by trigeminal neurones that are activated by noxious mechanical, thermal and chemical stimuli. In the human cornea, these stimuli evoke only sensations of pain. We have analysed the innervation pattern and the response to noxious stimulation of the cornea of trkA (-/-) mutant mice. Corneal nerves were stained with the gold chloride impregnation method. Corneal sensitivity to noxious stimuli was assessed by counting blinking movements evoked by von Frey hairs, topical application of saline at different temperatures and application of acetic acid and capsaicin at different concentrations. In the cornea of trkA (-/-) mutant animals, we observed a drastic reduction in the number of nerve trunks and branches in the corneal stroma. Furthermore, quantitative analysis of the number of thin nerve terminals revealed a marked decrease in the corneal epithelium of trkA (-/-) mice when compared to those present in wild type and trkA (+/-) animals. The blinking response of trkA (-/-) mice to mechanical, thermal and chemical noxious stimuli was also significantly reduced. These results indicate that the population of corneal sensory neurones is markedly depleted in trkA (-/-) mutant mice. However, a small portion of corneal sensory neurones survive in these mice suggesting that they may be NGF independent. On the basis of our results, we propose that these surviving cells are polymodal nociceptive neurones, sensitive to mechanical stimulation, noxious heat and acid.     

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.     

Regulation of the IL-12 receptor beta2 subunit by soluble antigen and IL-12 in vivo

Sympathetic innervation of lymphoid tissues is localized to specific tissue compartments, but little is known of the "factors" that are important in establishing this pattern during development. Numerous studies have shown interactions of nerve growth factor (NGF) with the immune system, which may include modulation of immune innervation. We previously have shown that NGF transgenic mice, which overexpress NGF in skin and not immune tissues, have a dramatic hyperinnervation of splenic marginal zone and peripheral lymph node medulla and capsule. The purpose of the current studies was to determine if the presence of elevated NGF would alter immune system development and the process of sympathetic ingrowth. The results show that the splenic innervation in NGF transgenics gradually diverged from controls during the first two postnatal weeks, with the greatest change occurring between postnatal days 13 and 16 when the splenic organization was reaching the adult pattern. In contrast, the peripheral lymph nodes were hyperinnervated at an earlier age. mesenteric lymph nodes never diverged from the normal pattern. NGF levels in transgenic spleen were much higher than controls at postnatal days 1 and 2, when little innervation was present, and declined as the tissue matured, possibly because of NGF uptake by the ingrowing sympathetic fibers. This suggests that immune tissues are capable of concentrating NGF, which in turn may modulate the level of innervation by the sympathetic nervous system.     

Responses of cutaneous A-fiber nociceptors to noxious cold

Responses of cutaneous nociceptors to natural stimuli, particularly mechanical and heat stimuli, have been well documented. Although nociceptors are excited by noxious cold stimuli, there have been few studies of their stimulus-response functions for cold stimuli over a wide range of stimulus temperatures. Furthermore, the proportion of nociceptors excited by noxious cold is not clear. In the present study, we examined responses of mechanosensitive A delta-nociceptors and low-threshold mechanoreceptors to a wide range of cold stimuli that included stimulus temperatures <0 degrees C. Electrophysiological recordings were made from single primary afferent fibers in the saphenous nerves of anesthetized rats. Cutaneous sensory receptors were classed according to their conduction velocity and subgrouped functionally according to their responses evoked by mechanical, heat, and cold stimuli (0 degrees C). Responses evoked by a wide range of cold stimulus intensities that included stimuli considered innocuous and noxious (painful) were then assessed. Stimuli of 20 to -20 degrees C were delivered to the receptive field via a 1-cm2 contact thermode from a base temperature of 32 degrees C. Stimuli were applied in descending order of 2 degrees C decrements. Stimulus ramp rate was 5 degrees C/s, and stimulus temperatures were applied for a duration of 10 s. A total of 90 A fibers was studied, of which 61 were nociceptors and had conduction velocity in the A delta-range (2-30 m/s). Nociceptors were classed initially as mechanical, mechanoheat, and mechanocold nociceptors. The remaining 29 fibers were low-threshold mechanoreceptors with conduction velocity in the A delta- or A beta-range (>30 m/s). These were subgrouped according to their adaptive properties as slowly or rapidly adapting, and according to whether they were excited by hair movement (hair follicle afferent fibers). All nociceptors were excited by noxious cold. Only 30% of nociceptors were considered sensitive to cold on initial classification with the use of a cold stimulus of 0 degrees C. However, all nociceptors were excited by stimulus intensities <0 degreesC. Response thresholds for cold ranged from 14 to -18 degrees C (-4.6 +/- 1.07 degrees C, mean +/- SE). The total number of impulses, discharge rate, and peak discharge increased monotonically as intensity of cold stimuli increased. Power functions were used to determine the rate at which the number of impulses increased as stimulus intensity increased. The slopes of power funcions ranged from 0.12 to 2.28 (mean 1.07 +/- 0.13). Most mechanoreceptors were not excited by cold stimuli. The only types of mechanoreceptors that responded reliably to cold stimuli were the slowly adapting mechanoreceptors. Responses usually occurred during the temperature ramp when the skin temperature was decreasing. There was no evidence that mechanoreceptors encoded the intensity of cold stimuli at intensities above or below 0 degrees C, because evoked responses did not increase with intensity of cold stimuli. It is concluded that the proportion of cutaneous A delta-nociceptors excited by noxious cold stimuli has been underestimated in previous studies. All nociceptors were excited by stimulus temperatures <0 degrees C and encoded the intensity of cold stimuli. It is therefore likely that cutaneous A delta-nociceptors contribute to the sensation of cold pain, particularly pain produced by stimulus temperatures <0 degrees C.     

Why perinatal mortality cannot be a proxy for maternal mortality

Although vasodilator agents have been used to alleviate the pain of complex regional pain syndromes, the precise mechanism of pain relief is not well known. In this study the effects of various kinds of vasodilators on primary afferent nociceptors were investigated by measuring the thermal pain threshold. Evaluated in the study were the effects of guanethidine (2 mg/mL), nicardipine (0.2 mg/mL). Nitroglycerin (0.3 mg/mL), and prostaglandin E1 (1 microgram/mL) on the cutaneous pain threshold and blood flow at 7-day intervals in six healthy volunteers. Each aliquot of 0.5 mL of the test vasodilator or lidocaine (10 mg/mL) and saline (control) were intradermally injected at three sites each on both forearms. The pricking-pain threshold and skin tissue blood flow were determined using a radiant heat-stimulating system and a laser-Doppler tissue-blood flowmeter, respectively. The pain threshold increased with lidocaine, guanethidine, and nicardipine; remained unchanged with Nitroglycerin; but decreased with prostaglandin E1. In contrast, the skin tissue blood flow increased by four to nine times with all vasodilators. These results indicate that the effect of vasodilators on primary afferent nociceptors is not related to the vasodilating effect and may not involve a common mechanism of action for pain relief in complex regional pain syndromes.     

Neural cell classification by wavelets and multiscale curvature

It has been postulated that the aberrant projection of sympathetic axons to individual primary sensory neurons may provide the morphological basis for pain-related behaviors in rat models of chronic pain syndrome. Since nerve growth factor (NGF) can elicit the collateral sprouting of noradrenergic sympathetic terminals, it might be predicted that NGF plays a role in mediating the sprouting of sympathetic axons into sensory ganglia. Using a line of transgenic mice overexpressing NGF among glial cells, it was first found that trigeminal ganglia from adult transgenic mice possessed significantly higher levels of NGF protein in comparison to age-matched wild-type mice; as well, detectable levels of NGF mRNA transgene expression were present in both the ganglia and brain stem. Within the trigeminal ganglia, a small proportion of the sensory neuronal population stained immunohistochemically for NGF; a higher percentage of NGF-positive neurons was evident in transgenic mice. New sympathetic axons extended into the trigeminal ganglia of transgenic mice only and formed perineuronal plexuses surrounding only those neurons immunostained for NGF. In addition, such plexuses were accompanied by glial processes from nonmyelinating Schwann cells. From these data, we propose that accumulation of glial-derived NGF by adult sensory neurons and its putative release into the ganglionic environment induce the directional growth of sympathetic axons to the source of NGF, namely, the cell bodies of primary sensory neurons.     

Adrenergic and nitrergic responses of the rat isolated anococcygeus muscle to a new toxin (makatoxin I) from the venom of the scorpion Buthus martensi Karsch

Muscle fibre composition was compared among the proximal (25%), middle (50%) and distal (75%) regions of muscle to investigate whether denervation induces region-specific changes of fibre types in the soleus and plantaris muscles of rats. Decreases in mass were observed in both muscles after denervation. In the soleus muscle, denervation increased the percentage of type I fibres with a concomitant increase in the proportion of type IIC and IIA fibres. The extent of such transformations was greater in the proximal region than the middle and distal regions. In normal plantaris muscle, the middle region showed a higher proportion of type IIA fibres with a lower percentage of type IIB fibres reciprocally than other regions. These regional differences in fibre types were not detected in the 4-week denervated plantaris muscle. These findings suggest that denervation-induced transformations from type I to type II fibres begin in the proximal region in the soleus muscle of rats. In addition, regional differences in fibre types along the muscle length could be regulated by neuromuscular activity through normal innervation in the plantaris muscle.     

Blindsight and visual awareness

Some patients with damaged striate cortex have blindsight-the ability to discriminate unseen stimuli in their clinically blind visual field defects when forced-choice procedures are used. Blindsight implies a sharp dissociation between visual performance and visual awareness, but signal detection theory indicates that it might be indistinguishable from the behavior of normal subjects near the lower limit of conscious vision, where the dissociations could arise trivially from using different response criteria during clinical and forced-choice tests. We tested the latter possibility with a hemianopic subject during yes-no and forced-choice detection of static and moving targets. His response criterion differed significantly between yes-no and forced-choice responding, and the difference was sufficient to produce a blindsight-like dissociation with bias-sensitive measures of performance. When measured independently of bias, his sensitivity to static targets was greater in the forced-choice than in the yes-no task (unlike normal control subjects), but his sensitivity to moving targets did not differ. Differences in response criterion could therefore account for dissociations between yes-no and forced-choice detection of motion, but not of static pattern. The results explain why patients with blindsight are apparently more often "aware" of moving stimuli than of static stimuli. However, they also imply that blindsight is unlike normal vision near threshold, and that pattern- and motion-detection in blindsight may depend on different sets of neural mechanisms during yes-no and forced-choice tests.     

Brief, prolonged and repeated stimuli applied to hyperalgesic skin areas: a psychophysical study

In this experimental study brief/prolonged and single/repeated, nociceptive stimuli (laser, thermode and electrical) were used to investigate sensory changes in capsaicin-induced primary and secondary hyperalgesia. The pain threshold to prolonged thermode stimulation was reduced in the primary area and remained constant in the secondary area. The pain thresholds to brief laser and electrical stimuli remained constant in the primary but reduced in the secondary area. The summation pain threshold to repeated (five stimuli delivered at 0.5, 1, 2 and 3 Hz) laser and electrical stimuli was reduced in the secondary area. The stimulus response functions to single laser and electrical stimuli were increased in the secondary area.