Maria Fitzgerald

The development of nociceptive circuits

The study of pain development has come into its own. Reaping the rewards of years of developmental and molecular biology, it has now become possible to translate fundamental knowledge of signalling pathways and synaptic physiology into a better understanding of infant pain. Research has cast new light on the physiological and pharmacological processes that shape the newborn pain response, which will help us to understand early pain behaviour and to design better treatments. Furthermore, it has shown how developing pain circuitry depends on non-noxious sensory activity in the healthy newborn, and how early injury can permanently alter pain processing.

Capsaicin and sensory neurones--a review.

In the late fifties and sixties Jancso published a series of papers on ‘the peculiar pharmacological effect of capsaicin Capsaicin or 8-methyl-N-vanillyi-6-nonenamide is the irritant compound in the capsicum plant (red pepper, chilli pepper, etc.). After initial violent irritation, capsaicin application renders animals and man insensitive to further noxious chemical stimuli. This desensitization can last for weeks or months following systemic administration in rats [47]. Despite this powerful effect, at that time, no clear-cut morphological lesion could be found to accompany it. In 1977, however, Jancso’s son and colleagues reported on the effects of capsaicin administered to neonatal rats. This was followed by a life-long insensitivity to chemical irritants accompanied by destruction of the small ‘B-type’ dorsal root ganglion cells [41]. It was this discovery that began a great surge of interest in the effects of capsaicin, in laboratories all over the world, producing the considerable amount of information that we have about its actions today. Its potential as a specific toxin for peripheral C fibres has made it of particular interest to neurobiologists concerned with pain mechanisms. This review was written as a result of a meeting on capsaicin in November 1981 at the Medical Research Council in London. At this meeting, neuroscientists of different disciplines who had used capsaicin in their research or studied its mode of action came together to discuss problems. Questions that arise out of the work so far, include: (1) Is the action of capsaicin on the peripheral nerve restricted to C fibres? (2) Does capsaicin have a direct effect on central nervous tissue? (3) Is capsaicin an axonal transport blocker? (4) What is the effect of capsaicin on nerve membrane? (5) Does capsaicin treatment result in analgesia? The following review shows to what extent we can answer these and other important questions about capsaicin. It is important too, in a general sense, to decide how useful a tool capsaicin is in understanding the nervous system and how much we have learnt from it so far. The review will be restricted almost completely to the somatosensory system. The effects of capsaicin on cardiovascular, respiratory, thermoregulatory and gastroin-

Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia.

&NA; The flexion reflex threshold has been used as a measure of sensation in a group of premature infants born at 27–32 weeks postmenstrual age. The threshold in an area of local tissue damage created by routine heel lances was half the threshold on the intact heel on the other side. This indicated a hypersensitivity to tissue damage analogous to tenderness or hyperalgesia reported in adults. In a double‐blind study, treatment of the damaged area with the topical anaesthetic cream, EMLA, was found to reverse this hypersensitivity or in other words increase the flexion reflex threshold. Treatment with placebo had no effect. The results show that the newborn infant central nervous system is capable of mounting a chronic pain response to local injury which can be reduced by local anaesthetic.

Cortical Pain Responses in Human Infants

Despite the recent increase in our understanding of the development of pain processing, it is still not known whether premature infants are capable of processing pain at a cortical level. In this study, changes in cerebral oxygenation over the somatosensory cortex were measured in response to noxious stimulation using real-time near-infrared spectroscopy in 18 infants aged between 25 and 45 weeks postmenstrual age. The noxious stimuli were heel lances performed for routine blood sampling; no blood tests were performed solely for the purpose of the study. Noxious stimulation produced a clear cortical response, measured as an increase in total hemoglobin concentration [HbT] in the contralateral somatosensory cortex, from 25 weeks (mean Δ[HbT] = 7.74 μmol/L; SE, 1.10). Cortical responses were significantly greater in awake compared with sleeping infants, with a mean difference of 6.63 μmol/L [95% confidence interval (CI) limits: 2.35, 10.91 μmol/L; mean age, 35.2 weeks]. In awake infants, the response in the contralateral somatosensory cortex increased with age (regression coefficient, 0.698 μmol/L/week; 95% CI limits: 0.132, 1.265 μmol/L/week) and the latency decreased with age (regression coefficient, −0.9861 μmol/L/week; 95% CI limits: −1.5361, −0.4361 μmol/L/week; age range, 25–38 weeks). The response was modality specific because no response was detected after non-noxious stimulation of the heel, even when accompanied by reflex withdrawal of the foot. We conclude that noxious information is transmitted to the preterm infant cortex from 25 weeks, highlighting the potential for both higher-level pain processing and pain-induced plasticity in the human brain from a very early age.

Nerve growth factor counteracts the neurophysiological and neurochemical effects of chronic sciatic nerve section

The sciatic nerve was sectioned unilaterally in rats and nerve growth factor (NGF) applied locally to the nerve stump for the following 10-14 days using an indwelling osmotic pump. The aim of the experiment was to test whether NGF had any effect on the previously reported neurophysiological and neurochemical events that occur central to a peripheral nerve lesion. The method of application allowed the sciatic nerve on the other side to be used as a control. Primary afferent depolarization fell, as expected, to 13% of its control value after chronic nerve section but if NGF was administered it fell to only 43.5% of control. Chronic nerve section is also known to result in expansion of the receptive fields of deafferented dorsal horn cells. NGF treatment reduced the number of such large receptive fields by 50%. The normal depletion of fluoride resistant acid phosphatase from the cut nerve terminals in the dorsal horn did not occur following NGF treatment. Radioimmunoassay of substance P revealed that the 30% reduction in dorsal horn levels that follows chronic sciatic nerve section did not occur when NGF was applied and that the accompanying 60% decrease in dorsal root ganglion levels was changed to a 64% increase by NGF. The results show that chronic NGF treatment of a cut sciatic nerve does partially reverse the central changes that normally follow deafferentation.

The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation

&NA; The threshold of a cutaneous withdrawal reflex, elicited by calibrated von Frcy hairs applied to the foot and leg, has been used to study the development of spinal sensory processing in a group of 50 preterm and full‐term infants ranging from 27.5 to 42.5 weeks postconceptional age (PCA). Data sets (108) were collected on initial threshold, the effects of repeated innocuous stimuli, the receptive field of the withdrawal reflex, and the effect of a contralateral stimulus. As reported previously (Fitzgerald et al. 1988, 1989), there was a correlation between PCA and initial threshold. The mean threshold at 29 weeks was 0.237 g (S.E.M. 0.042), whereas the mean threshold at 41 weeks was 0.980 g (S.E.M. 0.134). Repeated stimulation with von Frcy hairs led to a significant lowering of threshold or “sensitization” of the reflex in infants of up to 35 weeks PCA. Thereafter, the decrease in threshold was not significant, and habituation was observed. From 27.5 weeks PCA, it was possible to elicit the withdrawal reflex from the whole limb as far up as the top of the thigh and buttock. Below 30 weeks PCA, the thresholds within this receptive field were uniform, but after 30 weeks a gradient of thresholds was observed increasing progressively from the sole of the foot towards the knee. The application of a maintained stimulus to the contralateral limb significantly inhibited withdrawal reflex responses to ipsilateral von Frey hair stimulation, across all age bands. These results illustrate postnatal changes in sensory processing within the human spinal cord. Low thresholds over a large receptive field and sensitization on repeated stimulation suggest a lack of some, hut not all, inhibitory connections in the preterm neonate since contralateral inhibition is well established at birth.

The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord

The postnatal development of descending inhibition in the spinal cord has been studied in the rat. Electrophysiological recordings were made in neonatal rat pups of the activity in single lumbar dorsal horn cells evoked by stimulation of the skin of the hindlimb. Descending inhibition was tested by observing the effect of stimulation of the dorsolateral funiculus (DLF) at thoracic level on the dorsal horn cell responses. In adults the DLF is known to contain descending axons from the brainstem which inhibit dorsal horn cell activity. Such inhibition was always observed in days 22-24 rat pups. At 18 days of age it was present but required higher-intensity stimulation to produce an effect. On day 12 only half the dorsal horn cells tested were inhibited by DLF stimulation and then only weakly. On day 9 no cells were inhibited. Application of horseradish peroxidase to DLF axons in the lumbar cord resulted in retrograde labelling of cells in the medulla, pons and midbrain. The labelling on day 6 was comparable to the adult. The results show that despite the early anatomical existence of a descending DLF pathway, there is no functional descending inhibition until days 10-12 of life. It is suggested that this is due to delayed maturation of crucial interneurones in the dorsal horn or to insufficient levels of 5-hydroxytryptamine or other neurochemicals in the descending DLF axon terminals.

T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity

Partial peripheral nerve injury in adult rats results in neuropathic pain-like hypersensitivity, while that in neonatal rats does not, a phenomenon also observed in humans. We therefore compared gene expression profiles in the dorsal horn of adult and neonatal rats in response to the spared nerve injury (SNI) model of peripheral neuropathic pain. The 148 differentially regulated genes in adult, but not young, rat spinal cords indicate a greater microglial and T-cell response in adult than in young animals. T-cells show a large infiltration in the adult dorsal horn but not in the neonate after SNI. T-cell-deficient Rag1-null adult mice develop less neuropathic mechanical allodynia than controls, and central expression of cytokines involved in T-cell signaling exhibits large relative differences between young and adult animals after SNI. One such cytokine, interferon-γ (IFNγ), is upregulated in the dorsal horn after nerve injury in the adult but not neonate, and we show that IFNγ signaling is required for full expression of adult neuropathic hypersensitivity. These data reveal that T-cell infiltration and activation in the dorsal horn of the spinal cord following peripheral nerve injury contribute to the evolution of neuropathic pain-like hypersensitivity. The neuroimmune interaction following peripheral nerve injury has therefore a substantial adaptive immune component, which is absent or suppressed in the young CNS.

The neurobiology of pain: developmental aspects.

Invasive procedures that would be painful in children and adults are frequently performed on infants admitted to the neonatal intensive care unit. This article discusses sensory responses to these procedures in the immature nervous system and highlights the fact that, in addition to causing distress and delayed recovery, pain in infancy is also a developmental issue. First, the immaturity of sensory processing within the newborn spinal cord leads to lower thresholds for excitation and sensitization, therefore potentially maximizing the central effects of these tissue-damaging inputs. Second, the plasticity of both peripheral and central sensory connections in the neonatal period means that early damage in infancy can lead to prolonged structural and functional alterations in pain pathways that can last into adult life.

The postnatal physiological and neurochemical development of peripheral sensory C fibres.

The postnatal development of sensory C fibre function was investigated in neonatal rats aged 1-21 days. From birth, flexor-withdrawal reflexes (measured from the hamstring electromyograph) to pinching and heating the skin of the hindfoot were easily recorded under light anaesthesia and in fact were exaggerated in amplitude and duration compared to adult responses. Flexor reflexes to irritant chemicals, however, were not present until day 10-11 of life. In parallel with this late development of specific chemical sensitivity, neurogenic oedema, a C fibre-mediated inflammatory reaction, also did not occur until day 11. Substance P and fluoride-resistant acid phosphatase histochemistry were used to investigate the neurochemical development of sensory C fibres. Substance P was present in the skin, nerve, dorsal root ganglion and spinal cord from birth and fluoride-resistant acid phosphate within 12 h of birth. The adult neurochemical appearance of C-fibre terminals in the dorsal horn was established in a few days. The results show that despite the apparent early anatomical and neurochemical maturity of C fibres, physiological function is not fully established until the second week of life.