Spinal cord sensory systems after neonatal capsaicin

Animals with a severe reduction in the number of afferent C-fibres as a consequence of neonatal administration of capsaicin, exhibit a number of neurological and behavioral deficits including increased nociceptive thresholds, altered somato-visceral and viscero-visceral reflexes, depressed cardiovascular and respiratory reflexes and changes in the organisation of spinal cord sensory systems. The reduction in the number of C-fibres produced by neonatal capsaicin does not cause a decrease of similar magnitude in the number of dorsal horn cells driven by the surviving C-fibres. Twenty-two per cent of dorsal horn neurones in capsaicin treated animals respond to electrical stimulation of the surviving afferent C-fibres: a reduction of only 50% from control values. Inhibitory controls on afferent C-fibre evoked responses of dorsal horn neurones are weaker in capsaicin treated rate than in control animals. The cutaneous receptive fields of some dorsal horn neurones can increase in size following stimulation of afferent C-fibres. Tonic descending inhibition on C-fibre evoked responses of dorsal horn neurones is reduced in capsaicin treated rats: fewer neurones show tonic descending inhibition in these animals and those that do are subjected to less powerful inhibitions than similar neurones from control animals. However, some central inhibitory mechanism are unchanged after neonatal capsaicin treatment, specially those that do not involve afferent C-fibres. We suggest that the nervous system develops central inhibition in response to and directed towards the excitations mediated by its afferent drives. Therefore reduced central inhibition in response to a decreased number of afferent C-fibres can compensate for the lost capacity in the signalling of peripheral noxious events.     

The depolarising action of capsaicin on rat isolated sciatic nerve

The effect of capsaicin on the isolated sciatic nerve of rat was studied by extracellular recording of membrane polarisation. Capsaicin depolarised the sciatic nerve, but desensitization occurred rapidly upon repeated administration. Several other neuroactive substances, including substance P, were inactive. The depolarisation was reduced in nerves depleted of unmyelinated fibres by neonatal capsaicin treatment, suggesting that it occurs mainly in C-fibres. This depolarising action of capsaicin could explain the irritant and acute antinociceptive properties of capsaicin.     

C-fibres provide a source of masking inhibition to primary somatosensory cortex.

Capsaicin was applied to the exposed radial nerve of adult flying foxes (n = 5) and cats (n = 2) while recording in primary somatosensory cortex from a single neuron with a receptive field on digits 1 or 2. Within four minutes of application of capsaicin the borders of these receptive fields dramatically expanded. In a further four flying foxes it was shown, with subcutaneous delivery just proximal to the receptive fields, that capsaicin need affect only afferents from the region of a neuron's receptive field to induce expansion. Capsaicin applied directly to a nerve, or subcutaneously in high concentrations, is a selective neurotoxin that rapidly prevents the propagation of action potentials in most C-fibres. The result provides a partial explanation for experiments involving the specific and complete denervation of receptive fields of neurons in primary somatosensory cortex. Such denervation does not lead to unresponsiveness but to immediate sensitivity to stimulation of areas surrounding the original fields. Thus it appears that some subclass of capsaicin-sensitive C-fibres provides a primary source for the masking inhibition that normally limits the extent of the receptive fields of cortical neurons.     

Neurotoxic effect of capsaicin in mammals

Capsaicin is now widely used to explore and/or prove the role of peptide-containing primary afferent neurones in different somato- and viscerosensory functions. The present paper deals with the morphological effects of capsaicin administered according to currently used experimental paradigms. As it has been repeatedly confirmed in the recent literature, administration of capsaicin to newborn mammals results in a highly selective degeneration of a particular population of small sized, B-type primary afferent neurones located in spinal and cranial sensory ganglia. Chemosensitive i.e. capsaicin sensitive primary sensory neurones (CPSNs) correspond to primary sensory ganglion cells which contain neuropeptides. The permanent functional impairments and the decrease in the peptide contents of the sensory neurones observed after neonatal capsaicin treatment may be accounted for an irreversible loss of CPSNs. Direct application of capsaicin to peripheral nerves results in an apparently irreversible functional impairment of unmyelinated afferent fibres implicated in nociceptive, viscerosensory and neurogenic inflammatory mechanisms. Morphological observations indicate that perineural treatment with capsaicin initiates a selective but delayed degeneration process of unmyelinated afferent nerve fibres presumably due to an inhibition of intraneuronal transport mechanisms. In contrast with perineural capsaicin treatment affecting the chemistry and function of the whole sensory neurone, injection of capsaicin into the subarachnoid space results in an irreversible abolition of the "afferent" but not the "efferent" function of CPSNs. Accordingly, noxious thermal or chemical stimuli applied to the peripheral innervation areas of the trigeminal nucleus caudalis or the affected segments of the spinal cord fail to induce nociceptive reflexes because of the degeneration of the central terminals of CPSNs. However, in these same skin areas, application of chemical irritants invariably evoked the neurogenic inflammatory response, indicating that CPSNs deprived of their central terminals maintain their capacity to synthesize and release the peptide(s) responsible for the initiation of that response. In contrast with previous findings, our recent studies furnished evidence for a selective neurodegenerative action of systemically injected capsaicin in adult mammals, as well. Therefore, some of the irreversible functional impairments produced by capsaicin in adult animals may result from the degeneration of a particular subpopulation of CPSNs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ablation of primary afferent terminals reduces nicotinic receptor expression and the nociceptive responses to nicotinic agonists in the spinal cord

A variety of studies indicate that spinal nicotinic acetylcholine receptors modulate the behavioral and autonomic responses elicited by afferent stimuli. To examine the location of and role played by particular subtypes of nicotinic receptors in mediating cardiovascular and nociceptive responses, we treated neonatal and adult rats with capsaicin to destroy C-fibers in primary afferent terminals. Reduction of C-fiber terminals was ascertained by the loss of isolectin B4, CGRP and vanilloid receptors as monitored by immunofluorescence. Receptor autoradiography shows a reduction in number of epibatidine binding sites following capsaicin treatment. The reduction is particularly marked in the dorsal horn and primarily affects the class of high affinity epibatidine binding sites thought to modulate nociceptive responses. Accompanying the loss of terminals and nicotinic binding sites were significant reductions in the expression of α 3, α 4, α 5, β 2 and β 4 nicotinic receptor subunits in the superficial layers of the spinal cord as determined by antibody staining and confocal microscopy. The loss of nicotinic receptors that follows capsaicin treatment results in attenuation of the nociceptive responses to both spinal cytisine and epibatidine. Capsaicin treatment also diminishes the capacity of cytisine to desensitize nicotinic receptors mediating nociception, but it shows little effect on intrathecal nicotinic agonist elicited pressor and heart rate responses. Hence, our data suggest that α 3, α 4, α 5, β 2 and β 4 subunits of nicotinic receptors are localized in the spinal cord on primary afferent terminals that mediate nociceptive input. A variety of convergent data based on functional studies and subunit expression suggest that α 3 and α 4, in combination with β 2 and α 5 subunits, form the majority of functional nicotinic receptors on C-fiber primary afferent terminals. Conversely, spinal nicotinic receptors not located on C-fibers play a primary role in the spinal pathways evoking spinally coordinated autonomic cardiovascular responses.     

Calcitonin gene-related peptide is not essential for the development of pressure overload-induced hypertrophy in vivo.

The regulatory neuropeptide calcitonin-gene related peptide (CGRP) has been shown to evoke a hypertrophic response in isolated cardiomyocytes in vitro, an effect which was attributed to PKC activation. Activation of PKC has previously been implicated in the development of cardiac hypertrophy. We therefore investigated the role of CGRP in pressure overload-induced hypertrophy in vivo, which has not previously been reported. Constriction of the ascending aorta of rats resulted in an increase in the heart weight to body weight ratio, increased myocyte diameter, re-expression of the fetal genes ANF, MHCbeta and skeletal alpha-actin, and decreased expression of the adult genes GLUT4 and SERCA2a. Treatment of neonatal rat pups (1-2 days old) with capsaicin (50 mg/kg), resulted in the permanent de-afferentation of small-diameter unmyelinated CGRP-containing sensory C-fibres. Such treatment caused a 68% decrease in the CGRP-like immunoreactivity of hearts isolated from 10 week old rats (p < 0.001). Contrary to expectations, aortic constriction of capsaicin treated rats had no effect on the development of hypertrophy at the trophic, morphometric or gene expression levels. The results suggest that the development of pressure overload-induced hypertrophy in vivo does not require the regulatory neuropeptide CGRP.     

Individual characteristics of the nociceptive sensitivity of rats during the formation of a negative emotional reaction

Changes in dynamics of nociceptive sensitivity in male rats of Wistar strain were studied during formation of negative emotional reaction. The procedure of blood's taking from the tail after its tip's amputation was used as negative emotional factor. The animals were divided into six groups by the criterion of individual properties of nociceptive sensitivity dynamics. On the whole it was found to decrease. Besides, one more group (the seventh group) was found with profound hypoalgesia caused by action of the negative emotional factor. It was also shown that formation of negative emotional reaction in two groups was not accompanied by changes of nociception. The data suggest a selective influence of negative emotional factor on nociceptive sensitivity.     

Effect of 5,7-dihydroxytryptamine on pain sensitivity and analgesic activity of morphine

Electron microscopy of rats ultrathin sections from dorsal and central raphe nucleus and spinal cord after 5,7-dihydroxytryptamine intracisternal microinjection (200 micrograms) has revealed neurones and axonal terminals distruction, which associated with tail-flick hypoalgesia and blood pressure nociceptive reactions diminished. In this condition the morphine (2 mg/kg) analgesia and drug depressive effect on pain hemodynamic manifestations increase significantly.     

BDNF is essentially required for the early postnatal survival of nociceptors

Neurotrophins promote the survival of specific types of neurons during development and ensure proper maintenance and function of mature responsive neurons. Significant effects of BDNF (Brain-Derived Neurotrophic Factor) on pain physiology have been reported but the contribution of this neurotrophin to the development of nociceptors has not been investigated. We present evidence that BDNF is required for the survival of a significant fraction of peptidergic and non-peptidergic nociceptors in dorsal root ganglia (DRG) postnatally. Bdnf homozygous mutant mice lose approximately half of all nociceptive neurons during the first 2 weeks of life and adult heterozygotes exhibit hypoalgesia and a loss of 25% of all nociceptive neurons. Our in vitro analyses indicate that BDNF-dependent nociceptive neurons also respond to NGF and GDNF. Expression analyses at perinatal times indicate that BDNF is predominantly produced within sensory ganglia and is more abundant than skin-derived NGF or GDNF. Function-blocking studies with BDNF specific antibodies in vitro or cultures of BDNF-deficient sensory neurons suggest that BDNF acts in an autocrine/paracrine way to promote the early postnatal survival of nociceptors that are also responsive to NGF and GDNF. Altogether, the data demonstrate an essential requirement for BDNF in the early postnatal survival of nociceptive neurons.     

Effect of capsaicin on neuropeptides in areas of termination of primary sensory neurones

Capsaicin stimulates chemosensitive peripheral pain receptors, and neonatal administration produces degeneration of a population of primary afferent fibres. It has been shown previously that the effects of capsaicin are accompanied by the loss of substance P from areas of primary afferent termination and that enkephalin is not depleted from such areas. However, a number of other peptides are thought to be contained in sensory fibre systems and so we have used immunohistochemistry to examine the effect of capsaicin on the distribution of five different peptides in the substantia gelatinosa of the spinal trigeminal nucleus and spinal cord. Neonatal capsaicin treatment produces a depletion of somatostatin and cholecystokinin immunofluorescence in addition to substance P, but enkephalin and neurotensin immunofluorescence are not depleted. The implications of this result for theories of peptide involvement in nociceptive mechanisms are discussed.     

Role of L-DOPA in spinal nociceptive reflex activity: higher sensitivity of Aδ versus C fibre-evoked nociceptive reflexes to L-DOPA

The role of L-DOPA in spinal nociceptive reflex activity has been re-evaluated. In high spinal cats, with supraspinal loops being excluded, the onset of reflex facilitation induced by noxious radiant heat is delayed after injection of L-DOPA by 4 to 10 s, i.e. the early component of nociceptive reflex facilitation is blocked, while the late component persisted. Further investigations have shown that the early component of reflex facilitation induced by noxious radiant heat is mediated by Adelta-fibres and the late component by C-fibres. Therefore, it can be assumed that L-DOPA, like opioids, preferentially blocks the transmission in nociceptive reflex pathways from Adelta-fibres.     

Calcitonin gene-related peptide is not essential for the development of pressure overload-induced hypertrophy in vivo

The regulatory neuropeptide calcitonin-gene related peptide (CGRP) has been shown to evoke a hypertrophic response in isolated cardiomyocytes in vitro, an effect which was attributed to PKC activation. Activation of PKC has previously been implicated in the development of cardiac hypertrophy. We therefore investigated the role of CGRP in pressure overload-induced hypertrophy in vivo, which has not previously been reported. Constriction of the ascending aorta of rats resulted in an increase in the heart weight to body weight ratio, increased myocyte diameter, re-expression of the fetal genes ANF, MHC and skeletal -actin, and decreased expression of the adult genes GLUT4 and SERCA2a. Treatment of neonatal rat pups (1–2 days old) with capsaicin (50 mg/kg), resulted in the permanent de-afferentation of small-diameter unmyelinated CGRP-containing sensory C-fibres. Such treatment caused a 68% decrease in the CGRP-like immunoreactivity of hearts isolated from 10 week old rats (p < 0.001). Contrary to expectations, aortic constriction of capsaicin treated rats had no effect on the development of hypertrophy at the trophic, morphometric or gene expression levels. The results suggest that the development of pressure overload-induced hypertrophy in vivo does not require the regulatory neuropeptide CGRP.     

The Effect of Nimodipine on Calcium Homeostasis and Pain Sensitivity in Diabetic Rats

Summary 1. The pathogenesis of diabetic neuropathy is a complex phenomenon, the mechanisms of which are not fully understood. Our previous studies have shown that the intracellular calcium signaling is impaired in primary and secondary nociceptive neurons in rats with streptozotocin (STZ)-induced diabetes. Here, we investigated the effect of prolonged treatment with the L-type calcium channel blocker nimodipine on diabetes-induced changes in neuronal calcium signaling and pain sensitivity.2. Diabetes was induced in young rats (21 p.d.) by a streptozotocin injection. After 3 weeks of diabetes development, the rats were treated with nimodipine for another 3 weeks. The effect of nimodipine treatment on calcium homeostasis in nociceptive dorsal root ganglion neurons (DRG) and substantia gelatinosa (SG) neurons of the spinal cord slices was examined with fluorescent imaging technique.3. Nimodipine treatment was not able to normalize elevated resting intracellular calcium ([Ca²⁺] _i ) levels in small DRG neurons. However, it was able to restore impaired Ca²⁺ release from the ER, induced by either activation of ryanodine receptors or by receptor-independent mechanism in both DRG and SG neurons.4. The beneficiary effects of nimodipine treatment on [Ca²⁺] _i signaling were paralleled with the reversal of diabetes-induced thermal hypoalgesia and normalization of the acute phase of the response to formalin injection. Nimodipine treatment was also able to shorten the duration of the tonic phase of formalin response to the control values.5. To separate vasodilating effect of nimodipine Biessels et al., (Brain Res. 1035:86–93) from its effect on neuronal Ca²⁺ channels, a group of STZ-diabetic rats was treated with vasodilator – enalapril. Enalapril treatment also have some beneficial effect on normalizing Ca²⁺ release from the ER, however, it was far less explicit than the normalizing effect of nimodipine. Effect of enalapril treatment on nociceptive behavioral responses was also much less pronounced. It partially reversed diabetes-induced thermal hypoalgesia, but did not change the characteristics of the response to formalin injection.6. The results of this study suggest that chronic nimodipine treatment may be effective in restoring diabetes-impaired neuronal calcium homeostasis as well as reduction of diabetes-induced thermal hypoalgesia and noxious stimuli responses. The nimodipine effect is mediated through a direct neuronal action combined with some vascular mechanism.     

Mechanism of action of capsaicin-like molecules on sensory neurons.

Capsaicin produces pain by selectively activating polymodal nociceptive neurons. This involves a membrane depolarization and the opening of a unique, cation-selective, ion channel which can be blocked by ruthenium red. The capsaicin-induced activation is mediated by a specific membrane receptor which can be selectively and competitively antagonised by capsazepine. Repetitive administrations of capsaicin produces a desensitization and an inactivation of sensory neurons. Several mechanisms are involved. These include receptor inactivation, block of voltage activated calcium channels, intracellular accumulation of ions leading to osmotic changes and activation of proteolytic enzyme processes. Systemic and topical capsaicin produces a reversible antinociceptive and antiinflammatory action after an initial undesirable algesic effect. Capsaicin analogues, such as olvanil, have similar properties with minimal initial pungency. Systemic capsaicin produces antinociception by activating capsaicin receptors on afferent nerve terminals in the spinal cord. Spinal neurotransmission is subsequently blocked by a prolonged inactivation of sensory neurotransmitter release. Local or topical application of capsaicin blocks C-fibre conduction and inactivates neuropeptide release from peripheral nerve endings. These mechanisms account for localized antinociception and the reduction of neurogenic inflammation respectively.     

VEGF 164 gene transfer by electroporation improves diabetic sensory neuropathy in mice

BACKGROUND: Diabetic neuropathy is the most common cause of peripheral neuropathy and a serious complication of diabetes. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and has neurotrophic and neuroprotective activities. To examine the efficiency of VEGF 164 electro-gene therapy for neuropathy, intramuscular VEGF 164 gene transfer by electroporation was performed to treat sensory neuropathy in diabetic mice. METHODS: VEGF 164 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia, using a VEGF 164 plasmid injection with electroporation. From 2 weeks after electro-gene transfer, the nociceptive threshold was measured weekly using the paw-pressure test. The TA muscles, sciatic nerve, liver and spleen were histochemically examined at 4 weeks after electro-gene transfer. RESULTS: Two weeks after electro-gene transfer into the bilateral TA muscles, the elevated nociceptive threshold was decreased to a normal level in all treated mice. Improvement of the hypoalgesia continued for 14 weeks. When the VEGF 164 plasmid was injected with electroporation into a unilateral TA muscle, recovery from hypoalgesia was observed in not only the ipsilateral hindpaw, but also the contralateral one, suggesting that VEGF circulates in the blood. No increase in the number of endoneurial vessels in the sciatic nerve was found in the VEGF 164 plasmid-electroporated mice. CONCLUSIONS: These findings suggest that VEGF 164 electro-gene therapy completely recovered the sensory deficits, i.e. hypoalgesia, in the diabetic mice through mechanisms other than angiogenesis in the endoneurium of the peripheral nerve, and may be useful for treatment for diabetic sensory neuropathy in human subjects.     

The analgesic effect induced by capsaicin is enhanced in inflammatory states

Agonists of the vanilloid receptor type 1 (VR1), such as capsaicin, induce an analgesic effect following an initial excitatory response. It has been demonstrated that the vanilloid system plays an important role in inflammatory hyperalgesia. In accordance, we show that the VR1 antagonist capsazepine (30 microg; i.pl.) prevented the thermal hyperalgesia induced by carrageenan or complete Freund's adjuvant (CFA) in mice. Furthermore, we studied whether this inflammation-induced activation of the vanilloid system could enhance the analgesic properties of capsaicin. A single administration of capsaicin (10 microg; i.pl.) induced in control mice an analgesic effect that lasted for 2 days. In contrast, in carrageenan-treated animals, the analgesic effect of this dose of capsaicin lasted for 6 days and in CFA-treated mice for 30 days. This prolongation of capsaicin-induced analgesia during inflammation was mediated through VR1 since it was completely blocked by coadministration of capsazepine (10 microg). Licking behavior induced by capsaicin in carrageenan- and CFA-treated mice was greater than in control animals. However, although capsaicin induced a more prolonged analgesia in CFA-treated mice, the licking behavior was greater in the carrageenan-treated group, suggesting that the prolongation of analgesia is independent of the initial nociceptive input. Overall, these results show that the analgesic effects of capsaicin are importantly enhanced during inflammation, supporting the fact that the stimulation of VR1 could perhaps constitute a suitable strategy to avoid inflammatory hyperalgesia.     

Impaired capsaicin-induced decrease in heart rate and coronary flow in isolated heart of diabetic rats

The effect of capsaicin (0.1 microM) on heart rate and coronary flow was studied in Langendorff-perfused heart from streptozotocin-induced (50 mg/kg i.v.) diabetic rats where sensory neuropathy developed. In hearts from animals 4- and 8-week diabetes baseline heart rate and coronary flow decreased from 317.9 +/- 2.9 b.p.m. and 13.4 +/- 0.7 m/min to 255.1 +/- 12.7 and 219.8 +/- 2.8 b.p.m. and 8.9 +/- 0.6 and 10.0 +/- 0.1 ml/min (P<0.05), respectively. Capsaicin significantly decreased both variables in either normal or 4-week diabetic animals its effects, however, on coronary flow or heart rate were missing in preparations from 8-week diabetic rats. Endothelin-1 (0.1 nM), the putative mediator of the capsaicin effect, significantly decreased heart rate and coronary flow irrespective of the presence or absence of diabetes. In the femoral nerve of streptozotocin-treated animals conduction velocity involving both fast conducting A- and slow-conducting C-fibres was decreased proportional to the duration of the pre-existing diabetic state. It is concluded that in insulin deficient diabetes the diminished responses evoked by capsaicin on heart rate and coronary flow are signs of sensory neuropathy. This is related to a feeble endothelin release from sensory nerve endings without changes in post-receptor mechanisms mediating the endothelin effects.     

Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling

Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P-CTX-1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin-resistant, TRPA1-expressing peptidergic C-fibres and tetrodotoxin-sensitive A-fibres. P-CTX-1 does not directly open heterologously expressed TRPA1, but when co-expressed with Na_v channels, sodium channel activation by P-CTX-1 is sufficient to drive TRPA1-dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P-CTX-1 on TRPA1-deficient nociceptive C-fibres and of ciguatoxin-induced cold allodynia in TRPA1-null mutant mice. Functional MRI studies revealed that ciguatoxin-induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1-deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia.     

Involvement of a capsaicin-sensitive TRPV1-independent mechanism in lipopolysaccharide-induced fever in chickens

It has been demonstrated that capsaicin blocks lipopolysaccharide (LPS)-induced fever in mammals. In this study, we investigated TRPV1 (transient receptor potential ion channel of vanilloid subtype-1)-independent action of capsaicin on LPS-induced fever in chickens. The chicken is a valuable model for this purpose because chicken TRPV1 has been shown to be insensitive to capsaicin and thus the effects of capsaicin can be attributed to TRPV1-independent mechanisms. Administration of capsaicin (10 mg/kg, iv) to conscious unrestrained chicks at 5 days of age caused a transient decrease in body temperature. This effect of capsaicin was not observed in chicks that had been pretreated twice with capsaicin, indicating that the capsaicin-sensitive pathway can be desensitized. LPS (2 mg/kg, ip) induced fever that lasted for about 2.5 h, but fever was not induced in chicks that had been pretreated with capsaicin for 2 days. The preventive effect of capsaicin on LPS-induced fever was not blocked by capsazepine, an antagonist for TRPV1, but the antagonist per se blocked the febrile response to LPS. These findings suggest that a capsaicin-sensitive TRPV1-independent mechanism may be involved in LPS-induced fever.     

Developmental changes in threshold, conduction velocity, and depressive action of lignocaine on dorsal root potentials from neonatal rats are associated with maturation of myelination

Conduction velocity of primary afferent fibres and blocking actions of local anaesthetics seem to be developmentally regulated. The current work investigated physiological (threshold, conduction velocity, and myelination) and pharmacological (lignocaine (0.0625 to 2 mmol/L) and capsaicin (2 micromol/L)) ontogenic changes on in vitro sciatic nerve-dorsal root preparations from 0- to 12-day-old rats. As rats aged, stimulus intensities necessary to evoke A-fibre thresholds significantly decreased and A-fibre conduction velocities significantly increased. For C-fibres, thresholds significantly increased and conduction velocities significantly varied with age. The blocking potency of lignocaine varied with age: A-fibres from 4-day-old rats and younger were significantly more resistant than those from older rats, and C-fibres were blocked more uniformly amongst ages. Capsaicin significantly depressed C-fibres irrespective of age, and A-fibres were significantly reduced during the first postnatal week only. Myelination significantly increased as rats aged. A-fibre physiological parameters were significantly correlated with both other A-fibre physiological and pharmacological parameters, but C-fibre parameters were not. Peripheral A-fibre transduction mechanisms seem to require time to acquire their full stimulus-response sensitivity, which coincides with development of myelination. In contrast, peripheral C-fibres seem to have mature transduction mechanisms from the first days of postnatal life.