Cross-sectional areas and succinate dehydrogenase (SDH) activities of type identified fibres in the deep, middle and superficial regions of the tibialis anterior muscle in mice were examined after 4 weeks of voluntary running exercise with increasing loads. Nineteen-week-old male mice were assigned randomly to either a control or exercise group. The mean cross-sectional areas of all types (IIa, IIx and IIb) of fibres in the superficial region of the muscle were greater in the exercise group than in the control group. The mean SDH activities of type IIx and type IIb fibres in the middle region and of all types (IIa, IIx and IIb) of fibres in the superficial region of the muscle were greater in the exercise group than in the control group. These results suggest that voluntary running exercise with increasing loads causes hypertrophy and/or an increase in the SDH activity of fibres in the specific muscle region where fibres with a high threshold and a low-oxidative enzyme activity are distributed, and these fibres are recruited to adapt to changes in exercise conditions. Experimental Physiology (2002) 87.2, 113-116.

The induction of Fos protein was used to localise hypothalamic neurones activated by noxious somatic stimulation. This was combined with retrograde transport of fluorescent latex microspheres from identified 'pressor' and 'depressor' sites in the dorsolateral/lateral or ventrolateral columns of the periaqueductal grey (PAG). Fos-positive neurones were found throughout the rostral hypothalamus. Of those neurones activated by noxious somatic stimuli that projected to the PAG all but one was retrogradely labelled from sites that included the lateral column. Only one neurone was double labelled following injection of tracer at a depressor site in the ventrolateral PAG. This is in marked contrast to visceroresponsive hypothalamic neurones, a larger proportion of which project to the PAG and which, as reported previously, preferentially target depressor sites in the ventrolateral sector. These results are discussed in relation to the roles of the anterior hypothalamus and the different functional columns of the PAG in co-ordinating autonomic and sensory functions in response to nociceptive inputs originating in different peripheral domains. Experimental Physiology (2002) 87.2, 117-122.

The induction of Fos protein was used to localise hypothalamic neurones activated by ramps of noxious skin heating delivered at a rate of 2.5 °C s-1 to preferentially activate C-nociceptors. This was combined with retrograde transport of cholera toxin subunit B from identified 'pressor' and 'depressor' sites in the dorsolateral/lateral or the ventrolateral columns of the periaqueductal grey. Fos-positive neurones were found throughout the rostral hypothalamus. Despite this wide distribution, those neurones double labelled retrogradely from the periaqueductal grey were focused in the lateral area of the anterior hypothalamus. More than 20 % of Fos-positive neurones in this region projected to depressor sites in the ventrolateral periaqueductal grey, and 10 % projected to its dorsolateral/lateral sector. These results are discussed in relation to the peripheral inputs to hypothalamic-midbrain pathways and their role in the cardiovascular responses to different components of the pain signal. Experimental Physiology (2002) 87.2, 123-128.

The cellular mechanisms that underlie the initiation and propagation of the peristaltic contractions, which transport urine from the kidney to the bladder for storage, remain little understood. Extracellular and intracellular microelectrode recordings have identified two populations of smooth muscle cells as well as a population of renal interstitial cells (RICs) that all display spontaneous electrical activity. By analogy with the heart it has been proposed that atypical smooth muscle cells, preferentially located in the very proximal regions of the renal pelvis, generate the essential pacemaker signal. These pacemaker potentials propagate to neighbouring typical smooth muscle cells or RICs to trigger action potential discharge. These action potentials then propagate distally to trigger other bundles of typical smooth muscle cells. The frequency of action potential discharge and contraction decreases as the relative number of RICs and atypical smooth muscle cells compared to typical smooth muscle cells decreases with distance from the renal fornix. It is clear that functional capsaicin-sensitive sensory afferents and the endogenous release of both tachykinins and prostaglandins are essential in the maintenance of normal peristalsis, as well as in monitoring and responding to any chemical or mechanical stimulation. However, the cellular mechanisms underlying the action of these endogenously-released agents remain to be elucidated. Experimental Physiology (2002) 87.2, 129-146.

The muscarinic agonist bethanechol was infused intravenously, under α- and β-adrenoceptor blockade, in anaesthetized rats at various dose levels (5-10, 20 and 40-50 µg kg-1 min-1) over 30 min. The amount of saliva secreted from the parotid gland was dose dependent at 95, 202 and 737µl, respectively. The salivary amylase activity was approximately the same at the two lower doses (506 U and 448 U, respectively), while it was higher (1268 U) at the highest dose. In response to the highest dose, but not to the lower doses, the total parotid glandular amylase activity and the numerical density of parotid acinar secretory granules were lowered, by 25 % and 22 %, respectively. Thus, in the rat parotid gland, agonists such as bethanechol, which use Ca2+ as a second messenger, may release proteins not only by non-granular mechanisms but also, and in contrast to the general belief, by granule exocytosis. Experimental Physiology (2002) 87.2, 147-152.

The renal medulla contains more mRNA of the inducible isoform of nitric oxide synthase (iNOS) than the cortex, which may be important in preventing ischaemic injury, since blood flow and tissue oxygen tension are normally low in this region. We examined the effects of the bacterial endotoxin E. coli lipopolysaccharide (LPS) on renal function and regional expression of iNOS in male Sprague-Dawley rats. In six rats, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were 0.95 ± 0.09 ml min-1 g-1 and 3.36 ± 0.20 ml min-1 g-1, respectively, and decreased significantly to 0.35 ± 0.09 and 1.74 ± 0.54 ml min-1 g-1, respectively, 1 h after administration of LPS. In an additional seven rats, GFR and ERPF were 0.91 ± 0.07 and 2.97 ± 0.30 ml min-1 g-1, respectively, 18 h after LPS administration; these values were similar to those in control rats. In all rats, arterial pressure was stable throughout all study periods. In control rats, immunoblot analysis revealed expression of the iNOS protein in the cortex and more pronounced expression in the medulla. In rats studied 18 h after LPS treatment, there was a striking increase in the iNOS expression in the outer medulla. Immunohistochemical examination in the LPS-treated rats showed limited iNOS immunostaining in the cortex, localised to the vascular endothelium and macula densa; however, intense and widespread staining was noted in the tubular and vascular structures of the outer medulla. These findings demonstrated a differential constitutive expression of iNOS protein in different regions of the rat kidney, and marked augmentation of iNOS expression in the outer medulla by LPS. Experimental Physiology (2002) 87.2, 153-162.

Evans blue dye (EBD) conjugates with albumin in the circulation and is frequently used to measure vascular protein leakage. The fluorescence of the dye from tissue sections can be used to measure its uptake at very specific anatomical locations, but problems arise with dye quantification because tissue components also fluoresce; so-called autofluorescence. We have measured uptake of EBD by blood vessel walls at various points around the aorto-renal branch of rabbits. High resolution, digitised, fluorescence images of histological sections of artery wall allowed detailed microscopic analysis of EBD accumulation; and a ratiometric method was developed to enable autofluorescence to be separated from EBD fluorescence. When EBD-free tissue sections were illuminated with blue light, the ratio of red to green fluorescence was constant throughout the tissue (0.59 ± 0.03, mean ± S.D., n = 32). Therefore, at each individual pixel, the level of red autofluorescence could be determined by multiplying the green intensity at that pixel by the calculated red to green ratio. Since EBD fluorescence was detected only in the red region of the spectrum, intensity values of the dye alone were obtained from EBD-exposed tissue by subtracting the red autofluorescence estimated by this ratiometric method. In such cases the red to green fluorescence ratio was measured from adjacent sites known to be free of EDB (0.59 ± 0.02, mean ± S.D., n = 56). We were therefore able to increase the sensitivity of tracer quantification by complete elimination of background autofluorescence on a pixel-by-pixel basis. Use of EBD standards allowed calibration of corrected fluorescence intensities and calculation of mass transfer coefficients for albumin into the artery wall. Spatial variations in the permeability of the artery wall around the renal ostium were detected with the present high resolution technique, with an average mass transfer coefficient of (6.8 ± 0.9)×10-8 cm s-1 for all sites combined (n = 56). The present ratiometric method could potentially be applied to other quantitative fluorescence-based techniques. Experimental Physiology (2002) 87.2, 163-170.

In rings of rat iliac artery, contractions were evoked by noradrenaline (NA), the selective α1 adrenoceptor agonist phenylephrine (PE), and K+, which causes depolarisation-induced contraction. There was no evidence of α2 adrenoceptor-evoked contraction. Hypoxia, induced by reducing PO2 in the bath from 100 mmHg to 70, 55 or 40 mmHg, had similar effects on rings with (E+) and without (E-) endothelium. In E- rings, the NA concentration-response curve was biphasic, whereas that for PE was monophasic. Hypoxia reduced maximum contractions in response to NA and PE (NAmax and PEmax, respectively) without affecting the concentrations that evoked 50 % of maximum contraction (EC50). At PO2 of 70 mmHg, NAmax of the high affinity α1 receptor for NA (NAmaxh) and PEmax were reduced by ~15 %, but at PO2 of 55 and 40 mmHg, NAmaxh was severely attenuated while PEmax fell by 45 and 75 %, respectively. Similarly, the Ca2+ channel blocker nicardipine depressed NAmaxh and PEmax, but PO2 of 55 mmHg further reduced NAmax and PEmax. Hypoxia also reduced contractions evoked by NA, PE or K+ at the concentrations required to produce 80 % of the maximum contraction (EC80), receptor-mediated contractions being more affected. Ca2+-free conditions reduced the contractions evoked by NA and PE, at the EC80, to ~10 % of control. The K+ channel inhibitors glibenclamide and tetraethylammonium did not prevent hypoxia-induced depression of PE-evoked contraction. Thus, contractions evoked in iliac artery by the high affinity subtype of α1 adrenoceptor for NA, which may respond to circulating levels of NA, and by the single α1 adrenoceptor subtype for PE, are especially vulnerable to PO2 levels ≤ 55 mmHg. We propose that this reflects hypoxia-induced inhibition of Ca2+ influx through L-type and receptor-operated Ca2+ channels; K+ channel opening makes little contribution. Experimental Physiology (2002) 87.2, 171-184.

We have previously shown that extracellular fluid (ECF) is translocated by atrial contraction. Following on from this finding we have proposed a two-step sequential mechanism for the regulation of stretch-activated secretion of atrial natriuretic peptide (ANP): myocytic release of ANP into the surrounding paracellular space followed by the translocation of ECF with the released ANP into the bloodstream. This latter step is induced by atrial contraction, and is therefore controlled by atrial workload. However, the mechanism that regulates the changes in translocation of the ECF has not been defined. To define the relationship between the atrial workload, ECF translocation, size of the extracellular space (ECS) and ANP secretion, experiments have been performed in isolated perfused beating rabbit atria. Atrial workload, transendocardial translocation of the ECF and the secretion of ANP were quantified. Changes in the size of the atrium and the ECS were determined by a newly developed methodology in the beating atria. Atrial workload determined the translocation of the ECF and released ANP with waning of the translocation at higher myocardial workloads. Atrial workload inversely determined the size of the atrium and the ECS. The latter directly determined the translocation of the ECF in terms of atrial workload. From these data we suggest that the size of the ECS is an intimate modulator of the translocation of the ECF and released ANP, and that the phenomenon of waning of the transendocardial translocation that appeared at higher atrial workloads is closely related to the shrinkage of the ECS. Experimental Physiology (2002) 87.2, 185-194.

The aim of this study was to characterise the arrhythmogenic mechanisms involved in hypokalaemia-induced sustained ventricular fibrillation (SVF), in hypertensive rats. The hearts from rats with hypertension induced by the nitric oxide synthase inhibitor L-NAME, and age-matched normotensive controls, were perfused in Langendorff mode with oxygenated Krebs-Henseleit solution followed by a K+-deficient solution. In additional experiments, free intracellular Ca2+ concentration ([Ca2+]i) was measured using fura-2 in conjunction with an epicardial optical probe. The epicardial electrocardiogram was continuously monitored during all experiments. The gap junction protein connexin-43 and the ultrastructure of the cardiomyocytes were examined, and selected enzyme activities were measured in situ. There was a higher incidence of low-K+-induced SVF in the hearts of hypertensive compared to normotensive rats (83 % vs. 33 %, P < 0.05). Perfusion with a low-K+-containing solution lead to elevation of diastolic [Ca2+]i that was accompanied by premature beats, bigeminy, ventricular tachycardia and transient ventricular fibrillation. These events occurred earlier with increased incidence and duration in the hearts of hypertensive rats (arrhythmia scores: hypertensive, 4.9 ± 0.7; normotensive, 3.1 ± 0.1; P < 0.05), which exhibited apparent remodelling accompanied by a significant decrease in the density of connexin-43-positive gap junctions. Moreover, low-K+-related myocardial changes, including local impairment of intermyocyte junctions, ultrastructural alterations due to Ca2+ overload and intercellular uncoupling, and decreased enzyme activities were more pronounced and more dispersed in hypertensive than normotensive rats. In conclusion, nitric oxide-deficient hypertension is associated with decreased myocardial coupling at gap junctions. The further localised deterioration of junctional coupling, due to low-K+-induced Ca2+ disturbances, as well as spatial heterogeneity of myocardial alterations including interstitial fibrosis, probably provide the mechanisms for re-entry and sustaining ventricular fibrillation. Experimental Physiology (2002) 87.2, 195-205.

Previous studies have suggested that the uptake of prolactin from the blood into the milk may be restricted when the alveolus is distended with milk. Therefore the aim of this study was to determine the relationship between prolactin in milk and milk production by measuring the concentration of prolactin in samples of fore- and hind-milk as well as the volume of milk removed for each breast, at each breastfeed over a 24 h period. The mean (± S.D.) concentration of prolactin in milk for all women (n = 15) over the 24 h period was 18.5 ± 11.6 µg l-1 (fore-milk) and 16.8 ± 12.8 µg l-1 (hind-milk). The variation between women masked small changes within women in the concentration of prolactin in milk over the 24 h period, therefore a prolactin ratio (individual fore- or hind-milk value divided by the mean for all fore- or hind-milk samples collected over a 24 h period) was determined. The concentration of prolactin was highest in milk between 02.01 and 06.00 h (prolactin ratio for fore- to hind-milk, 1.5), and lowest between 10.01 and 18.00 h (prolactin ratio for fore- to hind-milk, 0.8). Furthermore, we observed that the difference in prolactin concentration between the fore- and hind-milk (fore-hind gradient) was greatest between 06.01 and 10.00 h (4 µg l-1). To ensure that this effect was not due to permeability in the paracellular pathway, the concentrations of serum albumin and sodium in milk were measured. No significant (P > 0.05) changes over the 24 h period, or with increasing time since last feed were observed. We therefore concluded that when the breast is most drained of milk (in the late evening), and the rate of milk synthesis is greatest, the fore-hind prolactin gradient in the milk of the following feed (in the early morning) is highest. This is consistent with the observation that prolactin uptake from the blood by the lactocyte is dependent on the fullness of the breast, such that prolactin uptake may be inhibited in full alveoli. Experimental Physiology (2002) 87.2, 207-214.

Several lines of evidence suggest that central serotoninergic neurons may mediate fatigue signals during prolonged exercise. In this study we examined the effects of diet and ambient temperature on peripheral modulators and indices of serotoninergic function and their relationship to exercise performance. Six well-trained cyclists participated, in randomised order, in two diet and exercise regimens each lasting 8 days and comprising four cycle tests to exhaustion at 70 % of maximum oxygen uptake. On days 1 and 5, subjects exercised to exhaustion to deplete muscle glycogen. For 3 days after the first depletion trial a diet providing 10 % of energy in the form of carbohydrate (CHO) was consumed (low CHO), and for 3 days after the second depletion trial a diet providing 80 % (high CHO) of energy as CHO was consumed, and each diet was followed by a performance trial at the same ambient temperature, either 10 °C or 30 °C (days 4 and 8). This schedule was repeated after 1 week, but performance trials were carried out at the other ambient temperature. In the cold, cycling time increased (P < 0.01) from 89.2 (78.0-129.5) min (median (range)) in the low CHO trial to 158.2 (116.9-165.6) min in the high CHO trial. In the heat, cycling time increased from 44.0 (31.8-51.4) min in the low CHO trial to 53.2 (50.2-82.2) min on the high CHO trial (P = 0.02). The serum prolactin (Prl) concentration was higher at exhaustion during the two trials in the heat than in the two trials in the cold. Serum Prl levels were unrelated to the purported peripheral modulators of serotoninergic function (plasma concentrations of total tryptophan (Trp), free Trp, branched-chain amino acids (BCAAs), free Trp/BCAA ratio and total Trp/BCAA ratio) but were significantly related to the rectal temperatures measured during the two trials in the heat. This finding provides indirect evidence that the serotoninergic system may be involved in fatigue during exercise under conditions of heat stress. Experimental Physiology (2002) 87.2, 215-226.

Leg muscles were occluded (33 kPa) prior to exercise to determine whether the induced metabolic changes, and reactive hyperaemia upon occlusion release just prior to the exercise, would accelerate the subsequent oxygen consumption (V˙O2) response. Eight subjects performed double bouts (6 min duration, 6 min rest in-between) of square wave leg cycle ergometry both below and above their lactate threshold (LT). Prior to exercise, large blood pressure cuffs were put around the upper thighs. Occlusion durations were 0 min (control), 5 min and 10 min. Ischaemia was terminated within 5 s prior to exercise onset. Heart rate, V˙O2, ventilatory rate (V˙E), electromyogram (EMG) and haemoglobin/myoglobin (Hb/Mb) saturation were recorded continuously. Single exponential modelling demonstrated that, compared to control (time constant = 53.9 ± 13.9 s), ischaemia quickened the V˙O2 response (P < 0.05) for the first bout of exercise above LT (time constant = 48.3 ± 14.5 s) but not to any other exercise bout below or above LT. The 3-6 min integrated EMG (iEMG) slope was correlated to the 3-6 min V˙O2 slope (r = 0.73). Hb/Mb saturation verified the ischaemia but did not show a consistent relation to the V˙O2 time course. Reactive hyperaemia induced a faster V˙O2 response for work rates above LT. The effect, while significant, was not large considering the expected favourable metabolic and circulatory changes induced by ischaemia. Experimental Physiology (2002) 87.2, 227-235.

Nociceptive dorsal root ganglion (DRG) neurones have fibres that conduct in the C, Aδ and Aα/β conduction velocity range. The properties of nociceptive compared with non-nociceptive somatic afferent dorsal root ganglion neurones appear to fall into two patterns, A and B. Pattern A properties of nociceptive neurones, the more common type, include longer action potential duration and slower maximum rate of fibre firing, as well as a greater expression of substance P and calcitonin gene-related peptide immunoreactivity. The values of pattern A properties appear to be graded according to the conduction velocity group (C, Aδ or Aα/β) of the fibres. The most pronounced forms of A-type properties are expressed by nociceptive neurones with C-fibres, and these become less pronounced in nociceptive neurones with Aδ-fibres and least pronounced in those with Aα/β fibres (C > Aδ > Aα/β). Some of these properties are also expressed in a less extreme but similarly graded manner through C, Aδ and Aα/β groups of non-nociceptive low threshold mechanoreceptive (LTM) neurone. The less common pattern B properties of nociceptive neurones have similar values in C-, Aδ- and Aα/β-fibre nociceptive neurones but these clearly differ from LTM units with C-, Aδ- and Aα/β-fibre conduction velocities. These features of nociceptive neurones include consistently larger action potential overshoots and longer after-hyperpolarisation durations in nociceptive than in LTM neurones. Experimental Physiology (2002) 87.2, 239-244.

The dorsal horn of the spinal cord plays an important role in transmitting information from nociceptive primary afferent neurones to the brain; however, our knowledge of its neuronal and synaptic organisation is still limited. Nociceptive afferents terminate mainly in laminae I and II and some of these contain substance P. Many projection neurones are located in lamina I and these send axons to various parts of the brain, including the caudal ventrolateral medulla (CVLM), parabrachial area, periaqueductal grey matter and thalamus. The neurokinin 1 (NK1) receptor on which substance P acts is expressed by certain neurones in the dorsal horn, including approximately 80 % of lamina I projection neurones. There is also a population of large NK1 receptor-immunoreactive neurones with cell bodies in laminae III and IV which project to the CVLM and parabrachial area. It has been shown that the lamina III/IV NK1 receptor-immunoreactive projection neurones are densely and selectively innervated by substance P-containing primary afferent neurones, and there is evidence that these afferents also target lamina I projection neurones with the receptor. Both types of neurone are innervated by descending serotoninergic axons from the medullary raphe nuclei. The lamina III/IV neurones also receive numerous synapses from axons of local inhibitory interneurones which contain GABA and neuropeptide Y, and again this input shows some specificity since post-synaptic dorsal column neurones which also have cell bodies in laminae III and IV receive few contacts from neuropeptide Y-containing axons. These observations indicate that there are specific patterns of synaptic connectivity within the spinal dorsal horn. Experimental Physiology (2002) 87.2, 245-249.

This review presents a schematic attempt to classify the major pain pathways, based on the results of recent studies in our laboratory, with a special emphasis on the parabrachial system. Our view is based on results from experiments in the rat, using very small iontophoretic injections of anterograde tracers. As illustrated in this report, we have found a very dramatic difference between ascending projections originating from deep laminae compared with those arising from lamina I of the dorsal horn. We propose three main pain systems and discuss their functional-anatomical relationships. The first system is centred on the projection from deep laminae to three caudal reticular areas - the lateral reticular nucleus (LRN), the subnucleus reticularis dorsalis (SRD) and the gigantocellular lateral paragigantocellular reticular nuclei (NGc) - and the parabrachial internal lateral subnucleus (PBil). The second system is centred on the projection from lamina I to the ventral posterolateral nucleus (VPL), the ventral posteromedial (VPM), the posterior nuclear group (Po) and triangular posterior nucleus (PoT) of the thalamus. The third system is centred on the projection from lamina I to the lateral parabrachial area. We also present the four main projections from the latter area to the extended amygdala, the hypothalamus, the periaqueductal grey matter (PAG), and the ventrolateral medulla (VLM), and their involvement in emotional and autonomic (homeostatic) aspects of pain. Experimental Physiology (2002) 87.2, 251-258.

Painful stimuli can evoke dramatic responses in the cardiovascular and respiratory systems. We have assessed the role of both the sympathetic and parasympathetic nervous system in mediating the reflex tachycardia that accompanies somatic nociception. We describe a major role for the nucleus tractus solitarii (NTS) as a site for integrating nociceptive and cardiorespiratory afferents. Since cardiorespiratory and nociceptive afferents terminate in the NTS, this nucleus offers a powerful opportunity for central modulation. We show that the NTS plays a major role in mediating the reflex tachycardia evoked by somatic noxious stimulation. Similar noxious stimulation attenuates the cardiac component of the peripheral chemoreceptor reflex and inhibits the peripheral chemoreceptor-evoked excitatory synaptic response of some NTS neurones. The functional interpretation we propose is that by depressing homeostatic reflexes at the NTS, noxious stimulation-evoked cardiorespiratory changes can be expressed and maintained, which may be essential for the survival of the animal. Experimental Physiology (2002) 87.2, 259-266.

The endogenous pain control system is composed of multiple functionally distinct brain regions, which are thought to integrate nociceptive information with various brain functions. The clear involvement of some pain control centres in cardiovascular modulation has been claimed as a strong indication of their role in nociceptive-cardiovascular integration. Particular emphasis has been given to their putative function in triggering cardiovascular reactions to pain. However, the possibility of their participation in the less-studied influence of cardiovascular conditions in pain perception has been largely ignored. We have recently addressed this issue by investigating the involvement of the caudal ventrolateral medullary reticular formation (cVLM) in hypertension-induced hypoalgesia. Circuits capable of conveying cVLM-elicited antinociception include a direct reciprocal cVLM-spinal loop, and two disynaptic spinal pathways relaying in rostroventromedial medullary (RVM) neurones and A5 noradrenergic neurones. In the three pathways, the cVLM neurones involved are circumscribed to a small area of reticular formation located laterally to the lateral reticular nucleus, the VLMlat. The VLMlat has a vasodepressor effect similar to that obtained from the cVLM. In the spinal cord dorsal horn, c-fos expression evoked by noxious stimuli is decreased in hypertensive animals, as compared to normotensive animals. In hypertensive animals following lesion of the VLMlat, spinal c-fos expression is identical to that observed in normotensive animals. The collected data point to a role for the VLMlat in the depression of spinal nociceptive processing in response to rises in blood pressure. Since hypertension-induced hypoalgesia is mediated by spinal α2-adrenoreceptors, this effect could be conveyed by the cVLM-A5-spinal pathway. Experimental Physiology (2002) 87.2, 267-274.

It is well established clinically that the affective response to pain of deep origin (muscles, joints and viscera) is distinct from that evoked by cutaneous pain. Cutaneous pain triggers a fight-flight reaction (active emotional coping), whereas deep pain evokes a reaction of quiescence, decreased vigilance and vasodepression (passive emotional coping). These observations led to suggestions of distinct central representations for deep versus cutaneous pain. Indeed, studies using immediate early gene (c-fos) expression revealed selective activation of ventrolateral versus lateral columns of the midbrain periaqueductal grey region (PAG) by persistent pain of deep origin versus intermittent cutaneous pain. Ventrolateral versus lateral PAG activation had been found earlier to evoke passive versus active emotional coping. However, not all cutaneous pain triggers active coping. Persistent cutaneous pain (e.g. burns) instead, usually evokes passive coping. This raised the question of whether the behavioural significance of pain (i.e. its escapability versus inescapability), rather than its tissue origin, is represented in supraspinal regions such as the PAG. Subsequent study revealed that a persistent (inescapable) noxious cutaneous manipulation (clip of the neck) evoked both selective ventrolateral PAG Fos expression and passive emotional coping. Such data suggest that pain representation in the PAG reflects a quality akin to behavioural significance, rather than tissue origin. In contrast, in the spinal cord predominantly superficial dorsal horn Fos expression was seen after either persistent or intermittent noxious cutaneous stimuli, leaving the question of the pathway(s) via which persistent (inescapable) cutaneous pain activates the vlPAG unanswered. One experimental approach to this question is suggested. Experimental Physiology (2002) 87.2, 275-279.

The affective responses to pain arising from deep somatic and visceral tissues differ markedly from those evoked by brief cutaneous insults. Deep pain evokes passive emotional coping that includes quiescence and vasodepression. In contrast, cutaneous pain evokes an active emotional coping: the fight or flight response. There is now considerable evidence to support the notion that nociceptive inputs arising from different peripheral domains drive the different functional columns of the periaqueductal grey (PAG) that co-ordinate either active or passive coping strategies. Nociceptive inputs from deep structures drive neurones in the ventrolateral columns that co-ordinate passive emotional coping whereas brief cutaneous insults activate the dorsolateral/lateral columns that co-ordinate active coping strategies. An emerging concept, as presented in the preceding article by Keay & Bandler, is that it is the behavioural significance of the nociceptive input, rather than its organ of origin per se, that determines the characteristics of the affective response. These authors provide evidence that brief, escapable stimuli activate neurones in the dorsolateral/lateral columns of the PAG and that inescapable, persistent pain, irrespective of its organ of origin, activates the ventrolateral column. This review will present recent evidence that differential representation of escapable and inescapable pain in the PAG extends to distinct representations of 'first' and 'second' pain, as indicated by the columnar distribution of neurones activated by inputs from Aδ- and C-nociceptors. Furthermore, the functional organisation of projections from circumscribed regions of the hypothalamus to the different columns of the PAG indicates that the behavioural significance of the pain signal is represented in brain regions other than the PAG. Experimental Physiology (2002) 87.2, 281-286.