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1. Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up-regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain. We have examined the effects of sodium channel blockers on mobility, joint hyperalgesia and inflammation induced by complete Freund's adjuvant injected in one ankle joint of adult rats. The clinically effective sodium channel blocker, mexiletine, was compared with crobenetine (BIII 890 CL), a new, highly use-dependent sodium channel blocker. 2. Rats were treated for 5 days, starting on the day of induction of arthritis and were tested daily for joint hyperalgesia, hind limb posture and mobility. At post-mortem, joint stiffness and oedema were assessed. Dose response curves were constructed for each test compound (3 - 30 mg kg day(-1)). Control groups were treated with vehicle or with the non-steroidal anti-inflammatory drug, meloxicam (4 mg kg day(-1) i.p.). 3. Both sodium channel blockers produced dose dependent and significant reversal of mechanical joint hyperalgesia and impaired mobility with an ID50 of 15.5+/-1.1 mg kg day(-1) for crobenetine and 18.1+/-1.2 mg kg day(-1) for mexiletine. Neither compound affected the responses of the contralateral non-inflamed joint, nor had any effect on swelling and stiffness of the inflamed joint. 4. We conclude that sodium channel blockers are analgesic and anti-hyperalgesic in this model of arthritis. These data suggest that up regulation of sodium channel expression in primary afferent neurones may play an important role in the pain and hyperalgesia induced by joint inflammation.

In this study, we have examined the effects of metamizol (dipyrone), a non-opioid analgesic which is effective in relieving renal colic pain, on nociceptive responses evoked by stimulation of the ureter, on pyeloureteral motility and on intraureter pressure after ureter obstruction in anaesthetised rats. Metamizol (5- 50 mg/kg i.v.) dose-dependently inhibited reflex pressor responses evoked by distensions of the ureter to pressures of 30, 55 and 75 mmHg for 30 s (ID50 = 8 +/- 1 mg/kg). Metamizol also dose-dependently reduced intraureter pressure during total ureter occlusion (25 mg/kg produced a reduction of 25% in 10 min). However, metamizol at doses up to 50 mg/kg had no effect on pyleoureteric motility (contraction amplitude, rate or intraureter pressure) under normal pressure conditions. We conclude that metamizol has a direct antinociceptive action on pain of ureteric origin, and spasmolytic effects after ureter obstruction (but not under normal conditions) which may also contribute to pain relief.

Substantial evidence suggests that the hyperalgesia to mechanical stimuli that occurs in an area of uninjured skin surrounding a site of injury (area of secondary hyperalgesia) arises from activity in low-threshold mechanoreceptors (LTMs). In this study, we have investigated if activity in mechanically sensitive nociceptors also contributes to this secondary hyperalgesia. It is known that all woollen fabrics excite LTMs, but that only the prickly ones activate mechanically sensitive nociceptors. Therefore, we have conducted a psychophysical study using a range of prickly and non-prickly woollen fabrics applied to normal and hyperalgesic skin to assess the roles of LTMs and nociceptors in secondary hyperalgesia. We have studied in 10 normal volunteers the sensations of fabric-evoked prickle and pain in normal and hyperalgesic skin. Secondary hyperalgesia was produced by intradermal injection of capsaicin (25 μg) into the volar skin of the forearm. Five woollen fabrics (2 non-prickly, 2 prickly and 1 intermediate) were presented, in a blind manner, to the skin before and after the capsaicin injection. The sensation of fabric-evoked prickle was not changed in hyperalgesic skin. On the other hand, little if any pain was evoked by the fabrics when applied to normal skin, but substantial pain was produced by all fabrics when applied to hyperalgesic skin. The pain ratings were graded with the ratings of prickle so that fabrics that evoked the greatest prickle also evoked significantly more pain. The magnitude of pain increased linearly with prickle sensation; the slope of this regression function increased substantially in hyperalgesic skin. The increased pain produced by prickly fabrics in the hyperalgesic skin exceeded that which could be predicted by the acquired capacity of LTMs to evoke pain plus the pain produced by the prickly fabrics in normal skin. We conclude that the central alterations responsible for secondary hyperalgesia involve two components: an acquired capacity of LTMs to evoke pain and an increased responsiveness of central neurones to input from mechanically sensitive nociceptors.

A study was undertaken to determine the segmental organization of the dorsal root ganglion cells which give rise to ureteric primary afferent fibres in the guinea-pig. The size-distribution and peptide content of these dorsal root ganglion cells were examined and compared with a sample of all dorsal root ganglion cells from the same ganglia. Afferent fibres to the guinea-pig ureter were found to arise mainly from dorsal root ganglia L2-L3 and S1-S2. A large contralateral component of the afferent innervation of the ureter was found when either the right or the left ureter was injected with tracer. This amounted to approximately 40% of the total labelled cells. The cross-sectional areas of the dorsal root ganglion cells of ureteric afferents were found to be at the smaller end of the size-range for the whole ganglion. Most (90%) of the cells innervating the ureter were immunoreactive for one of the peptides studies, substance P or calcitonin gene-related peptide, and a large proportion (65%) were immunoreactive for both. This was very different for the ganglia as a whole, where only about 50% of the cells were immunoreactive for either of the peptides and only 14% were immunoreactive for both peptides. These results show a bilateral afferent innervation of the ureter by nerve fibres which, in the vast majority, contain substance P and/or calcitonin gene-related peptide.

1. In 15 alpha-chloralose-anesthetized cats we studied the presence of tonic descending inhibition (TDI) of spinal neurons with input from the knee and its modulation during an acute inflammation of this joint. TDI of spinal neurons with articular input was assessed by applying reversible cold blocks to the lower thoracic cord. The amount of descending inhibition was estimated from the induction and/or increase of resting discharges and of the responses to mechanical stimuli to the knee and other structures during the transitory and reversible blocks. In each experiment one or a few neurons were investigated while the joint was in normal condition [altogether 15 nociceptive-specific (NS) and 6 wide-dynamic-range (WDR) neurons]. One of the neurons was then selected for long-term recordings during which an acute inflammation in the knee was induced by the intra-articular injection of kaolin and carrageenan. Before and during developing arthritis, cold blocks were applied to examine whether the amount of TDI would change during the inflammatory process. 2. The neurons with input from the normal knee were under TDI because application of the cold block induced or increased resting discharges and the responses to noxious compression of the knee and the adjacent thigh and lower leg. In 10 of 15 NS neurons, the response threshold was lowered into the innocuous range. In 9 of 17 cells tested, the excitatory receptive field expanded to the ipsilateral paw, and 4 neurons became inhibited by paw compression. Seven of 18 neurons tested revealed inhibitory receptive fields on the contralateral leg during cold block. The neurons were located in laminae IV-VII. 3. Fourteen neurons were continuously monitored during development of inflammation, and changes in the effectiveness of TDI were assessed by blocking the cord before and during the development of arthritis. In most neurons baseline resting activity in the intact state of the cord increased while the arthritis developed. This inflammation-evoked enhancement of resting discharges was more pronounced during periods of spinalization. Consequently, the differences between the resting discharges in the cold-blocked and the intact state were progressively enhanced in arthritis. 4. After induction of arthritis, the responses to compression of the knee joint increased in the intact state as well as during cold blocks. In 11 of 14 neurons, the differences between the responses in the spinal and intact state were progressively enlarged during the development of inflammation. A similar result was obtained for flexion of the injected knee.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute visceral pain is dull, aching, ill-defined, badly localized and often referred to remote areas of the body. These properties indicate that the representation of internal organs within the CNS is very imprecise. There is evidence for the existence of specific visceral nociceptors in some viscera and for the existence of non-specific receptors in other internal organs. Some visceral receptors are 'silent' in normal viscera but become active following acute injury or inflammation of the internal organ that they innervate. The number of nociceptive afferent fibres in viscera is very small but these few nociceptive afferents can excite many second order neurones in the spinal cord which in turn generate extensive divergence within the CNS, sometimes involving supraspinal loops. Such a divergent input activates several systems--sensory, motor and autonomic--and thus triggers the general reactions that are characteristic of visceral nociception: a diffuse and referred pain, and prolonged autonomic and motor activity.

From the beginning of scientific enquiry there have been two opposing views on the biological meaning of pain. One view proposes that pain is a sense similar to vision or hearing, a component of the sensory repertoire of most animals that warns us of impending damage, gives accurate information to the brain about injuries, and helps us to heal. The inclusion of pain in The Senses: A Comprehensive Reference, alongside vision, hearing, or olfaction shows that this view is persuasive. But there has always been an alternative interpretation of pain that denies it being a sense like vision or hearing and attaches to both pain and its opposite pleasure fundamental roles in shaping the emotions and behaviors of the individual. Pain is seen as a trigger of emotional states, a behavioral drive, and a highly effective learning tool. Aristotle, who was the originator of this view, made it very clear: there are only five senses – vision, hearing, touch, taste, and smell. Pain and pleasure are not senses but passions of the soul.

Visceral pain is the most common form of pain produced by disease and one of the most frequent reasons for patients to seek medical attention. Yet much of what we know about the basic mechanisms of pain derives from experimental studies of somatic nociception. This would be justified if the mechanisms of somatic and visceral pain were similar so that information obtained by studying one form of pain could be extrapolated to interpret the mechanisms of the other. However, the more we know about the mechanisms of somatic and visceral sensation the more we realise that these two processes, while having many common features, also have important differences. We seldom have any sensory experiences from our internal organs other than pain and discomfort and even when other sensations occur, such as bladder or stomach fullness, these can easily evolve towards pain if the stimulus persists. The five main characteristics of visceral pain—that is, those clinical features that make visceral pain unique—are that visceral pain1: (i) : is not evoked from all viscera, (ii) : is not linked to visceral injury, (iii) : is referred to other locations, (iv) : is diffuse and poorly localised, and (v) : is accompanied by motor and autonomic reflexes. Properties (i) and (ii) generated the notion that some viscera lacked an afferent innervation. We now know that …

We examined whether stimulation of sensitive mechanoreceptors from an area of allodynia evokes nociceptor activity expressed as axon reflexes. Experiments were conducted on human volunteers. Cutaneous blood flow was measured with a laser Doppler flowmeter. Allodynia was induced with mustard oil (25-100%) or by intradermal injections of capsaicin (25-50 micrograms) in the skin of the forearm or the hand. Tactile stimulation of normal skin or outside zones of allodynia did not evoke axon reflexes. The same stimulation in areas of allodynia evoked pain as well as axon reflexes. Cooling the area of primary hyperalgesia or blocking the A fibres in the nerve that innervated the allodynia area abolished the allodynia and the axon reflex. These results demonstrate central interactions between sensitive mechanoreceptors and nociceptors concomitant with the development of allodynia.

1. Single-unit extracellular recordings were made from thirty-one dorsal horn neurones in the sacral spinal cord of barbiturate-anaesthetized rats. Each neurone was tested with four noxious mechanical pinches applied to its receptive field on the tail. Each pinch lasted 120 s, with a step-like change in intensity after 60 s. In two pinches the step increased the intensity, from 4 to 6 N or from 6 to 8 N, and in two the step decreased the intensity, from 8 to 6 N or from 6 to 4 N. 2. The ability of the neurones to signal these step changes in intensity was examined. Five neurones with an exclusively low-threshold afferent input (class 1) were tested, and found to fire only briefly at the start of the 120 s stimulus. Neurones with a high-threshold input (nociceptive neurones), either exclusively (class 3; n = 10) or in addition to a low-threshold input (class 2: n = 16), responded throughout the 120 s stimuli. 3. Nociceptive dorsal horn neurones have been divided into two groups of 'good' and 'poor' encoders on the basis of their response to the step changes in intensity. 4. 'Good' encoders (n = 13) were neurones signalling both a step increase and a step decrease in intensity, of which seven were class 2 and six class 3, five recorded in the superficial dorsal horn and eight in the deep dorsal horn. 5. 'Poor' encoders (n = 13) were neurones which failed to signal one or both of the step changes in intensity, of which nine were class 2 and four class 3, three recorded in the superficial dorsal horn and ten in the deep dorsal horn. 6. These results demonstrate that neurones with similar input properties and location are not necessarily a homogeneous group in terms of their processing of nociceptive stimuli. Moreover, they suggest that subgroups of both class 2 and class 3 and of superficial and deep dorsal horn neurones contribute to the different components of a nociceptive response. 7. We propose that the output and projection target of a particular dorsal horn neurone are more important than its afferent input in determining its role in nociceptive processing.

In ten cats, single unit electrical activity was recorded in the lumbosacral spinal cord from neurones driven by stimulation of afferent fibres from the ipsilateral knee joint. Tonic descending inhibition (TDI) on the responses of these cells was measured as increases in resting and evoked activity of the neurones following reversible spinalization of the animals with a cold block at upper lumbar level. Acute inflammation of the knee joint was induced in five of the cats by the injection of kaolin and carrageenan into the joint. TDI was observed in 25 of 33 neurones recorded in normal animals (76%) and in 36 of 40 (90%) neurones recorded in animals with acute knee joint inflammation. In both kinds of preparation TDI was more pronounced in neurones recorded in the deep dorsal horn and in the ventral horn than in those recorded in the superficial dorsal horn. There was a tendency in the whole sample for TDI to be greater in neurones with input from inflamed knees. We conclude that the spinal processing of afferent information from joints is under tonic descending influences and that the amount of TDI can be altered during acute arthritis.

One of the most important considerations in restorative proctocolectomy for ulcerative colitis is postoperative continence. Preservation of the anal transition zone has been associated with improved results after this procedure in the pediatric age group. This study was carried out to determine the effect of preservation of the amal transition zone in adult patients undergoing restorative proctocolectomy, comparing a group of patients with the anal transition zone preserved with a group of patients with the anal transition zone removed. Physiologic testing demonstrated improved sensation in those patients with a preserved anal transition zone. Functional results were not significantly improved, although there was a trend toward improved continence and discrimination in those with the anal transition zone preserved. Although the results are early and are not conclusive from the clinical standpoint, they are certainly encouraging and may justify continued use of this technique.

Single unit electrical activity has been recorded from viscerosomatic neurons in the lower thoracic spinal cord of decerebrate spinalized cats. The responses of the cells to electrical stimulation of afferent fibres in the splanchnic (SPLN) nerve and the effects of repetitive stimulation of somatic and visceral afferent C-fibres have been studied. Four groups of viscerosomatic neurones could be distinguished according to the type of visceral afferent input of the cells: (1) A-only cells (32.9%), driven only by stimulation of A delta afferent fibres in the SPLN nerve; (2) C-only cells (3%), driven only by stimulation of C afferent fibres in the SPLN nerve; (3) A + C cells (45.7%), driven by both A delta and C afferent fibres in the SPLN nerve; and (4) A + C? cells (18.6%), driven by A delta visceral afferents and showing signs of responsiveness to C-fibres though lacking a distinct response volley to visceral C-fibre activation. Two cells of the A + C group and located in lamina I of the dorsal horn responded to SPLN nerve stimulation in a manner consistent with the afferent fibre composition of the nerve, that is, showed evidence of strong monosynaptic links with SPLN afferent C-fibres and weaker responses to SPLN A delta afferents. Excitability changes of viscerosomatic neurones ('wind up', 'wind down' and changes in background activity) were also observed in the majority of neurones following electrical stimulation of somatic and of visceral afferent C-fibres.(ABSTRACT TRUNCATED AT 250 WORDS)

The only non-general sensation that can be evoked from the gastrointestinal (GI) tract is that of pain ranging from mild discomfort to intense pain. However, in certain regions of the gut, such as the rectum and gastro-oesophagus, the feeling of pain can be preceded by non-painful sensations of distension at lower stimulus intensities. GI pain is often dull, aching, ill-defined and badly localized. In some cases, GI pain is projected to areas of the body away from the originating viscus ('referred' pain). These properties indicate that the representation of internal organs within the central nervous system is very imprecise. Behavioural, neurophysiological and clinical evidence shows that most forms of GI pain are mediated by activity in visceral afferent fibres running in sympathetic nerves and that the afferent innervation of the gut mediated by parasympathetic nerves is not primarily concerned with the signalling and transmission of GI pain. As for the encoding mechanism of the peripheral sensory receptor in the gut, there is evidence for the existence of specific visceral nociceptors in some locations (e.g. the biliary system) and for the existence of non-specific 'intensity' type receptors in other locations (e.g. the colon). In any case, the actual number of nociceptive afferent fibres in the gut is very small and this explains why large areas of the GI tract appear to be insensitive or require considerable stimulation before giving rise to painful sensations. The few nociceptive afferents contained in sympathetic nerves can excite many second order neurones in the spinal cord which in turn generate extensive divergence within the spinal cord and brain stem, sometimes involving long supraspinal loops. Such a divergent input can activate many different systems, motor and autonomic as well as sensory, and thus trigger the general reactions that are characteristic of visceral nociception: a diffuse and ill-localized pain sometimes referred to somatic areas, and autonomic and somatic reflexes that result in prolonged motor activity.

1. Single-unit electrical activity has been recorded from dorsal horn neurones in the sacral (S1-S2) segments of the spinal cord of barbiturate-anaesthetized rats. Fifty-two neurones responding to a manually applied pinch of their receptive fields in the tail were selected. They were subsequently tested for their responses to four successive 2 min pinches at noxious intensities delivered by a feed-back-controlled mechanical device. 2. Neurones were tested with both innocuous (i.e. brushing and stroking) and noxious (i.e. pinching, pin-prick, and in some cases heating about 45 degrees C) stimulation of their cutaneous receptive fields. Three of the tested cells were driven exclusively by innocuous skin stimulation (mechanoreceptive or class 1), thirty-six were driven by both innocuous and noxious skin stimulation (multireceptive or class 2) and thirteen were driven exclusively by noxious skin stimulation (nocireceptive or class 3). 3. All of the multireceptive and nocireceptive neurones responded to the 2 min noxious pinch with an initial phasic discharge followed by sustained firing that showed little evidence of adaptation throughout the stimulus period. The three mechanoreceptive neurones responded to the 2 min noxious pinch with a short discharge at the stimulus onset, but were silent for the remainder of the stimulus period. 4. Thirty-one cells were tested with successive 2 min pinches of 4, 6 and 8 N (and in some cases, a further 4 N pinch) applied at 10 min intervals. Different encoding properties were observed during the sustained part of the neuronal response according to: (i) the afferent fibre input characteristics of the cell; (ii) whether or not the tail had received a test series of pinches earlier in the same experiment. 5. None of the multireceptive cells with only an A-fibre afferent input encoded the stimulus strength. However, the multireceptive cells with both an A- and a C-fibre afferent input and all nocireceptive cells did encode the stimulus strength, providing that no previous noxious test stimuli had been applied to the tail. The encoding nocireceptive neurones had in general a steeper stimulus-response curve than the encoding multireceptive neurones, though the two groups overlapped to some extent. 6. Three encoding cells (two multireceptive and one nocireceptive) were tested with a second series of pinches (4, 6, 8 and 4 N), 40 min subsequent to the initial test series. These cells did not encode this second test series, but were more excitable, producing a greater response to a given test force.(ABSTRACT TRUNCATED AT 400 WORDS)

Visceral nociceptive thresholds, viscero-visceral reflexes and the effects of efferent stimulation of autonomic nerves have been studied in adult rats treated at birth with capsaicin. These animals showed visceral analgesia and depressed visceral reflexes. However, stimulation of unmyelinated efferent fibers in autonomic nerves produced normal effects. It is concluded that neonatal treatment with capsaicin destroys selectively unmyelinated afferent fibers.

1. Intersegmental dorsal root potentials (d.r.p.s) have been recorded in the lumbar spinal cord of spinalized cats under Na pentobarbitone anaesthesia, to investigate the spinal cord structures involved in the intersegmental transmission of d.r.p.s. 2. A technique has been developed for restricted surgical isolation of Lissauer's tract between the segments with subsequent histological verification of the extent of the isolation. 3. Section of the ipsilateral dorsal column resulted in an increase in the latency of the intersegmental d.r.p. and a significant reduction in its amplitude. A further reduction in amplitude was achieved by section of the ipsilateral dorso-lateral funiculus. 4. Neither section of Lissauer's tract after the above lesions were performed nor restricted Lissauer's tractotomies abolished intersegmental d.r.p.s; only a small reduction in the amplitude of the d.r.p. was obtained. 5. It is proposed that intersegmental d.r.p.s are produced by the activaiton of a propriospinal system projecting through pathways other than Lissauer's tract and that primary afferent collaterals from the dorsal columns make a major contribtuion to their generation. The contribution made by Lissauer's tract is probably small.

In the skin, temperature sensation plays an important role in discriminating between gas, liquid and solid. To elucidate the role of temperature sensation in idiopathic faecal incontinence we studied the minimum detectable temperature change in the lower, middle and upper zones of the anal canal anal rectum in 33 normal subjects, and 20 patients with idiopathic faecal incontinence. A water perfused thermode was used to vary anorectal temperature from 37°C down to 32.5°C and up to 41.5°C. The temperature change was reported by the patient as the thermode temperature varied from 37°C to each extreme and on return to base line. The anal canal in the control group was highly sensitive to temperature change, the lower rectum was significantly less sensitive (P

Thermal and mechanical nociceptive thresholds and somato-visceral reflexes have been studied in normal rats and in rats treated neonatally with capsaicin. Mechanical nociceptive thresholds were increased in capsaicin treated rats whereas thermal nociceptive thresholds remained unchanged. In contrast, somato-visceral reflexes evoked by thermal noxious stimulation of the skin could not be elicited in capsaicin treated rats whereas mechanical noxious stimulation was effective in evoking visceral reflexes.

Extracellular single-unit recordings were made from 121 neurones in the thoracic spiral cord of the cat. All neurones could be driven by electrical stimulation of dorsal root afferent fibres. The neurones were classified, according to the absence or presence of inputs from the ipsilateral splanchnic nerve, as “somatic” or “viscerosomatic,” respectively. Cutaneous receptive fields were identified for 75 of the neurones: 31 were somatic and 44 viscerosomatic. Only two of the somatic cells received cutaneous nociceptive inputs, compared with 33 of the viscerosomatic cells. Sixty-four percent of the whole sample of neurones had receptive fields which included three or more dermatomes. Viscerosomatic cells tended to have larger receptive fields than the somatic neurones, and six of them had fields which did not include the corresponding (T11) dermatome. Neurones with receptive fields in the dorsal one-third of the dermatome tended to be located in the lateral one-third of the dorsal horn, but those with receptive fields in the ventral two-thirds of the dermatome showed no differential distribution within the gray matter. This is discussed with respect to the results of anatomical studies on the dorsal horn projections of cutaneous afferent fibres from different regions of the dermatome. Preliminary results from intracellular staining with horseradish peroxidase reveal extensive branching of primary afferents in the dorsal horn, and large dendritic fields of dorsal horn neurones. Our physiological and morphological results indicate that the somatotopic organisation of the thoracic spinal cord is less well defined than that of the lumbosacral region.

1. Single-unit electrical activity has been recorded from 42 dorsal horn neurons in the sacral segments of the rat's spinal cord. The sample consisted of 20 multireceptive (class 2) cells with both A- and C-fiber inputs and 22 nocireceptive (class 3) cells. All neurons had cutaneous receptive fields (RFs) on the tail. 2. The RF sizes of the cells and their response thresholds to mechanical stimulation of the skin were determined before and after each of a series of 2-min noxious mechanical stimuli. Up to five such stimuli were delivered at intervals ranging from 10 to 60 min. In most cases, only one cell per animal was tested. 3. The majority of neurons were tested in barbiturate-anesthetized animals. However, to test whether or not this anesthetic influenced the results obtained, experiments were also performed in halothane-anesthetized and decerebrate-spinal preparations. The results from these experiments are considered separately. 4. All of the neurons responded vigorously to the first noxious pinch stimulus and all but one to the rest of the stimuli in the series. The responses of the neurons varied from stimulus to stimulus, but there were no detectable trends in the two groups of cells. 5. The RFs of the class 2 cells showed large increases (624.3 +/- 175.8 mm2, mean +/- SE) after the application of the pinch stimuli. The RFs of the class 3 neurons, which were initially smaller than those of the class 2 cells, either did not increase in size or showed very small increases after the pinch stimuli (38.3 +/- 11.95 mm2, mean +/- SE). 6. Some cells in both groups (6/10 class 2 cells and 7/16 class 3 cells) showed a decrease in mechanical threshold as a result of the noxious mechanical stimulus, but none of the class 3 cells' thresholds dropped below 20 mN into the low-threshold range. 7. The results obtained in the halothane-anesthetized and decerebrate-spinal animals were very similar to those seen in the barbiturate-anesthetized experiments, with the exception that in the decerebrate-spinal animals, the RFs of the class 2 cells were initially larger and showed only small increases.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Single unit electrical activity has been recorded extracellularly from 133 neurones in the grey matter of the 8th and 9th thoracic segments of the spinal cord in chloralose anaesthetized cats. The responses of these neurones to electrical stimulation of the ipsilateral splanchnic nerve, to natural stimulation of the skin and to distension of the biliary system have been studied.2. Of the neurones studied, 75% responded to electrical stimulation of the splanchnic nerve and had a cutaneous receptive field in the costal region (viscero-somatic neurones). Twenty-three per cent of the neurones had a cutaneous receptive field but no visceral input (somatic neurones) and 2% had a visceral input but no cutaneous field.3. Somatic neurones had well-localized receptive fields from which they could be driven by innocuous stimulation of the skin (52%), by noxious (7%) or by both forms of stimulation (41%). No somatic neurones projected to supraspinal levels via the contralateral ventro-lateral funiculus.4. Viscero-somatic neurones were excited by small myelinated and non-myelinated afferent fibres in the splanchnic nerve. Most viscero-somatic neurones had cutaneous inputs from nociceptors either exclusively (38%) or in addition to non-noxious inputs (53%).5. The recording sites of somatic neurones were located almost exclusively in laminae II and IV and dorsal V of the dorsal horn. In contrast, viscero-somatic neurones were located in lamina I and in laminae V-IX of the grey matter. No differential distribution of recording sites according to type of cutaneous receptive field has been found within the viscero-somatic group of neurones.6. About one-third of all viscero-somatic neurones could be excited by distensions of the biliary system. In all cases, intensities of visceral stimulation above physiological levels were necessary to activate the neurones. Most units driven by biliary afferents were located in or ventral to lamina V of the dorsal horn. The excitation of these units by biliary distension was found to be specifically mediated by receptors in the biliary system.7. Sixteen per cent of the neurones were found to project to supraspinal levels via crossed ventro-lateral pathways. All of these neurones were viscero-somatic with axonal conduction velocities between 12 and 68 m sec(-1).8. These results are discussed in relation to the postulates of the ;Convergence-projection' theory of referred pain.

1. Activity of single spinocervical tract neurones has been recorded in the lumbar spinal cord of chloralose anaesthetized or decerebrated cats. Reversible spinalization was produced by cold block at L3. Sensitivity of these neurones to noxious stimulation was studied by heating their cutaneous receptive fields above 40-45 degrees C. 2. Most of the units were located in lamina IV of the dorsal horn and had their receptive fields in the ipsilateral foot. All but one of the studied neurones were excited by moving hairs or by gentle mechanical stimulation of the skin. 3. Eighty-four % of the units were affected by noxious stimuli and three kinds of response were obtained: (i) 61% were excited (E-cells) by noxious heat; (ii) 19% were inhibited (I-cells); and (iii) 19% gave a mixed response reversing from excitatory to inhibitory (EI-cells). 4. E-cells had axons with a wider range of conduction velocities than the rest and also received the strongest descending inhibition from supraspinal structures. 5. The recording sites of EI-cells were located in the medial third of the dorsal horn whereas E- and I-cells were distributed over the full width of the dorsal horn. 6. The possible role of the spinocervical tract in nociception is discussed.

A visceral afferent origin of substance P-like immunoreactivity in lamina V of the lower thoracic spinal cord of the rat was investigated. In transverse sections from normal animals there was a moderately dense substance P-immunoreactive innervation of lamina V. In some sections there was a dorsoventrally orientated fibre bundle from the superficial dorsal horn entering lamina V. In parasagittal sections, substance P-immunoreactivity in lamina V was found arranged in clusters, with a periodicity in the rostrocaudal axis of 200–600 μm. In some cases these were seen to be continuous with a dorsoventrally orientated fibre bundle from the superficial dorsal horn. After section of the splanchnic nerve there was a consistent reduction in the density of the substance P-like immunoreactivity in lamina V, with fewer clusters on the operated side. Adult rats treated neonatally with capsaicin showed a substantial reduction of substance P-immunoreactivity in laminae I and II and the virtual abolition of staining in lamina V. These results provide evidence of a visceral origin for some of the substance P-like immunoreactivity in lamina V of the rat thoracic spinal cord. In addition, they confirm that most of the substance P-immunoreactivity in the dorsal horn is of primary afferent origin.

1 Baroreceptor and chemoreceptor reflex activity was studied in anaesthetized adult rats which had been treated neonatally with a single injection of capsaicin (50 mg/kg s.c.). 2 Pressor responses to bilateral carotid artery occlusion were significantly lower in capsaicin-treated rats compared with vehicle-treated controls. Pressor responses to intravenously injected noradrenaline were similar in the two groups of rats. 3 Resting respiratory minute volume and tidal volume were lower in anaesthetized capsaicin-treated animals than in vehicle-treated controls, but there was no significant difference in respiratory frequency. 4 The increases in respiration evoked by intravenous administration of the peripheral arterial chemoreceptor stimulant, sodium cyanide, or by breathing a hypoxic gas mixture, were significantly lower in capsaicin-treated rats compared with the controls. 5 It is concluded that baroreceptor and chemoreceptor reflex activity are significantly reduced in anaesthetized adult rats which had been treated neonatally with capsaicin, and that this is likely to result from the destruction of unmyelinated baro- and chemoreceptor afferent fibres.

1. Electrophysiological recordings from ureteric mechanosensitive afferent fibres were performed using an in vitro preparation of the guinea-pig ureter and associated nerves. Single-unit recordings were obtained from small ureteric nerves arising from the inferior mesenteric ganglion, the hypogastric nerve or the pelvic plexus. The fibre composition of these ureteric nerves was also examined by electron microscopy. 2. In two ureteric nerve bundles, which were taken as representative of the maximal and minimal size of nerves used in the electrophysiological recordings, the number of nerve fibres was found to be 417 and 48, respectively. In the bigger nerve 12% of the fibres were small myelinated and the rest unmyelinated. The smaller nerve consisted of unmyelinated fibres only. 3. Electrophysiological recordings were made from sixty-seven mechanosensitive afferent fibres. The conduction velocities (CV) of forty-two of them were determined and all were found to be in the C fibre range (mean CV, 0.4 m/s). Of 119 additional fibres which were not further characterized 112 were C fibres (mean CV, 0.51 m/s) and seven were A delta fibres (mean CV, 3.78 m/s). 4. Mechanosensitive units were classified into two groups according to their ability to respond to contractions of the ureter: (i) U-1 units (9% of all mechanosensitive units) responded to contractions of the ureter and did not show on-going activity or after-discharges to mechanical stimulation. They had low thresholds to intraluminal distension (mean, 8 mmHg) and responded with a short latency to pressure stimuli. (ii) U-2 units (91% of all mechanosensitive units) did not respond to contractions of the ureter, had spontaneous activity between 0 and 2.4 Hz and exhibited after-discharges to mechanical stimuli lasting up to several minutes. They responded after a long latency (greater than 3 s) to distensions in the range of 5-30 mmHg. 5. The level of spontaneous activity and the pressure thresholds of the U-2 units were found to be different depending on whether or not the ureter was perfused intraluminally. Thus U-2 units recorded with intraluminal perfusion had a lower rate of on-going activity and higher threshold to intraluminal distension than U-2 units recorded without intraluminal perfusion. 6. Movement of an intraluminal glass bead under the receptive field of the units evoked strong responses in nine of eleven U-2 units tested as soon as their receptive fields were reached. 7. Our results demonstrate the existence of two classes of mechanosensitive afferent fibres in the guinea-pig ureter.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Single-unit activity has been recorded from eighty-three viscero-somatic neurones in the lower thoracic spinal cord (T9-T11) of chloralose-anaesthetized cats. These neurones were driven by natural and/or electrical stimulation in their somatic receptive fields and gave excitatory responses to electrical stimulation of the ipsilateral splanchnic nerve. Contralateral visceral inputs were tested by electrical stimulation of the contralateral splanchnic nerve. Tonic and phasic descending influences were tested by reversible spinalization with cold block at T7 and by electrical stimulation in nucleus raphe magnus and the immediately adjacent reticular formation. 2. Most viscero-somatic neurones (89%) gave an excitatory response to stimulation of the contralateral splanchnic nerve and were therefore considered to have bilateral visceral inputs. In this group of neurones three categories of cells were identified depending on whether their responses to ipsilateral splanchnic nerve stimulation were decreased (50%), increased (42%) or unchanged (8%) in the spinal state. Only one cell with an exclusively ipsilateral visceral input was tested for the effects of reversible spinalization. Stimulation of contralateral splanchnic nerve failed to evoke activity in this cell in the spinal state. 3. Sixty-four viscero-somatic neurones with bilateral visceral inputs and four neurones with exclusively ipsilateral visceral inputs were tested with electrical stimulation in nucleus raphe magnus and the adjacent reticular formation. Seventy-eight per cent gave an initial excitatory response which was followed by a period of reduced responsiveness to stimulation of visceral and somatic afferents. Three of the four neurones with an exclusively ipsilateral visceral input had no excitatory drive from the brain stem but their responses to stimulation of visceral and somatic afferents were depressed. 4. The majority (77%) of neurones with bilateral inputs were located in laminae VII and VIII with the remainder in the dorsal horn, predominantly laminae I and V, whereas all but one of the neurones with an exclusively ipsilateral visceral input were located in the superficial dorsal horn, predominantly lamina I, and none in laminae VII and VIII. 5. These results show that the majority of viscero-somatic neurones in the cat's lower thoracic spinal cord receive bilateral visceral inputs and that the transfer of this information is subjected to descending control which includes excitation as well as inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)

Single unit electrical activity has been recorded from dorsal horn neurones in the lumbar cord of rats anaesthetized with sodium pentobarbitone. Three groups of animals were used: normal adult rats, adult rats that had been treated at birth with capsaicin (50 mg kg-1 s.c.) and adult rats that had been injected at birth with the drug vehicle only. Rats treated at birth with capsaicin showed a substantial reduction in the number of afferent C fibres as indicated by the virtual absence of C waves in the compound action potentials evoked in the sural nerve by antidromic stimulation of the L4-L6 dorsal roots. No significant differences were found in any of the parameters measured between the vehicle treated and the untreated animals. Therefore, rats from these two groups are referred to as control animals. All dorsal horn neurones studied were driven by electrical stimulation of the A fibres in the ipsilateral sural nerve and had cutaneous receptive fields in the ipsilateral hind limb. Two groups of neurone were distinguished: those receiving an input from A fibres only (A only) and those neurones that could also be driven by sural C fibres (A + C). In the control group, 56% of the neurones were A only and 44% were A + C. In capsaicin-treated rats these proportions were significantly different: 78% and 22% respectively. No differences were found in receptive field sizes of A-only neurones between those recorded in control rats and those from capsaicin-treated animals. However, a large and significant increase in receptive field size of A + C neurones was observed in capsaicin-treated rats compared to their counterparts in normal animals. In control rats 80% of the A + C neurones showed tonic descending inhibition of their C-fibre-evoked responses as assessed by reversible spinalization. In capsaicin-treated rats this proportion fell to 47% of the A + C neurones. The magnitude of the tonic descending inhibition was also reduced in the fewer A + C neurones of capsaicin-treated rats that were subjected to it. Only 4% of A + C neurones with tonic descending inhibition in capsaicin-treated rats were powerfully inhibited compared to 26% in control animals. The mean number of spikes evoked by C-fibre stimulation of the sural nerve in A + C neurones of control and of capsaicin-treated rats was not significantly different between these two groups of animals in the intact and in the spinalized states.(ABSTRACT TRUNCATED AT 400 WORDS)

Single unit electrical activity has been recorded from 29 viscero-somatic neurones in the T11 spinal cord segment of chloralose anaesthetized cats. Twenty-six of these neurones showed changes in their responses to electrical stimulation of the splanchnic nerve after reversible spinalization of the animals by cold block: 14 showed increased responses whereas 12 presented reduced or abolished responses during the spinal block. The majority of neurones in the first group were located in laminae IV, V and VII and were inhibited by electrical stimulation of the nucleus raphe magnus (NRM) and the reticular formation (Ret.F). Most neurones of the second type were located in the ventral horn, and the majority were excited by electrical stimulation of the NRM and the Ret.F. This second type of neurone may play a role in the maintenance of the excitation in the central nervous system which follows visceral noxious stimulation.

Anterograde transport of horseradish peroxidase (HRP) through somatic and visceral nerves was used to estimate the proportions of somatic and visceral dorsal root ganglion (DRG) cells of the lower thoracic ganglia of the cat. A concentrated solution of HRP was applied for at least 5 hours to the central end of the right greater splanchnic nerve and of the left T9-intercostal nerve of adult cats. Some animals remained under chloralose anaesthesia for the duration of the HRP transport time (up to 53 hours) whereas longer HRP application and transport times (4-5 days) were allowed in animals that recovered from barbiturate anaesthesia. Visceral DRG cells were found in approximately equal numbers in all ganglia examined (T7-T11). Population estimates were obtained for the T8 and T9 ganglia where visceral DRG cells were found to be 6.2% (T8) and 5.2% (T9) of the total cell population. In contrast, somatic DRG cells were found in large numbers in the ganglia examined (T8 and T9) where they amounted to over 90% of the cell population. Measurement of cross-sectional areas and estimates of cell diameters of the DRG cells showed greater proportions of large somatic cells (diameter greater than 40 micron) than of large visceral cells. Similar distributions of cell size were found for both somatic and visceral DRG cells with diameters less than 40 micron. These results show that the proportion of visceral afferent fibres in the dorsal roots that mediate the spinal cord projection of the splanchnic nerve is very small. Since viscerosomatic convergence in the thoracic spinal cord is very extensive, the present results suggest considerable divergence of the visceral afferent input to the central nervous system.

Single unit electrical activity has been recorded from neurons in the Th8 and Th9 segments of the spinal cord in chloralose-anesthetized cats. These neurons had cutaneous receptive fields in the right costal region from which they could be driven by noxious and/or innocuous stimulation of the skin. They could also be activated by distensions of the biliary system but only at noxious intensities of visceral stimulation. No viscero-somatic convergent neurons have been found responding to innocuous visceral stimulation.

Single unit electrical activity has been recorded from neurones in the Substantia Gelatinosa Rolandi (SG) of the lumbar spinal cord of chloralose anaesthetized and gallamine paralysed cats. SG neurones were identified on the basis of five previously defined criteria [Cervero, Iggo and Molony, 1979b]. The surface of the spinal cord containing Lissauer's tract was stimulated electrically in order to excite axons running through Lissauer's tract. In about half of the animals studied Lissauer's tract was in addition surgically isolated by sectioning the adjacent dorsal column and dorso-lateral funiculus. The responses of 32 intracellularly recorded and 78 extracellularly recorded SG neurones to stimulation of Lissauer's tract and surrounding structures have been analysed. Ten SG neurones had axons in Lissauer's tract that projected for distances between 15 and 41 mm (two and three segments rostral to their origin). The majority of the SG neurones studied did not project beyond their segments of origin. The mean conduction velocity of the long projecting SG neurones was 10·3 m.s-l (range 4·6–18·3 m.s−1), corresponding to conduction in small myelinated fibres. All 110SG neurones studied were excited post-synaptically by stimulation of Lissauer's tract and evidence is given to support the view that it was monosynaptically mediated. The latencies and threshold of the post-synaptic activation indicated that it was mediated by a group of Aδ fibres within Lissauer's tract. All SG neurones studied showed a long period of inhibition (200–500ms) following the initial excitation. This inhibition was mediated by large myelinated fibres since it appeared at stimulus intensities that were threshold for excitation of the largest dorsal column or dorso-lateral funiculus fibres. When axons in Lissauer's tract were recruited by electrical stimulation the period of inhibition lasted as long as 1s. The segmental somatotopic organization of the SG neurones was found to be similar to the larger dorsal horn neurones of the same spinal cord segments.

That the axons of lamina I cells travel towards the brain has been known since Kuru detected their retrograde chromatolytic response following cordotomy. However, it was not until the introduction of modern anatomical methods that the problem of the superficial dorsal horn’ connections with the brain could be addressed with precision. We now know that lamina I cells innervate a very large number of targets in the medulla, pons, thalamus (including distinct targets in lateral, medial, and caudal nuclei), hypothalamus, and several regions of the telencephalon. The papers in this section review the progress that has been made in mapping the brain regions that are innervated by superficial dorsal horn cells and present exciting new observations on the development, morphology, and neurochemistry of lamina I cells.

Ventromedial forebrain structures were stimulated electrically with short (10-ms) trains of pulses to test for effects on a viscerosomatic reflex. Stimulation at many hypothalamic sites led to an attenuation or even a complete inhibition of reflex activity. The most sensitive sites, however (i.e. those requiring currents of 50 μA or less to inhibit the reflex), were located in the anterior hypothalamus/preoptic area (AH/POA) and rostrally in the diagonal band of Broca (DBB). At certain sites the effects of electrical stimulation were compared with those of microinjection of an excitatory amino acid (DL-homocysteic acid) which is known to excite neuronal cell bodies and not axons. The results of this part of the study indicated that activation of cell bodies located in the ventromedial AH/POA (from the level of the optic chiasma caudally to the level of DBB rostrally) mediate, at least in part, the inhibitory effects on visceral afferent processing. These data are discussed in relation to a possible role of AH/POA in the spinal processing of nociceptive information of visceral origin.

1. The afferent innervation of the distal ileum has been examined in normal rats and in rats treated at birth with capsaicin. Electrophysiological recordings were made using an in vitro preparation of distal ileum and its associated mesenteric nerves. The fibre composition of the mesenteric nerves was examined by electron microscopy and the numbers of primary afferent fibres innervating a segment of distal ileum was estimated using retrograde tracing. 2. Recordings were made from 120 single afferent units all of which showed some degree of background activity. The conduction velocities of sixty-seven afferent units were estimated, and all were found to be in the C-fibre range (less than 2 m/s). Eighty-two units were sufficiently studied to allow their classification according to whether they responded to mechanical stimuli (M units), chemical stimuli (Ch units) or both mechanical and chemical stimuli (MCh units). In control rats 85.5% were classified as MCh units, 11.9% as M units and 2.6% as Ch units. In capsaicin-treated rats six single and three multi-units were MCh and one multi-unit was classified as an M recording. 3. The effects of intraluminal distension were investigated in sixty-seven units which were classified according to whether or not they adapted during the distension. About half the total units were classified as rapidly adapting, the other half were slowly adapting. This distribution was similar for the MCh-units, but of the eight M units tested, seven adapted during distension. The distension thresholds were tested in thirty units, of which twenty-eight responded at thresholds below 18 mmHg. There were no differences in the thresholds of units from control and capsaicin-treated rats. 4. The chemosensitivity of units was tested in response to acetylcholine (ACh), bradykinin and substance P. Most units tested responded to ACh (78% of MCh units tested) and bradykinin (80% of MCh units), but fewer units responded to substance P (about 50% of MCh units). ACh produced an increased tension which outlasted the increase in afferent activity. Bradykinin gave long-lasting afferent responses which were not always accompanied by increases in tension. The increases in afferent activity produced by substance P were often seen after an increase in tension. 5. The fluorescent dye True Blue injected into the wall of the ileum labelled cell bodies in the spinal and nodose ganglia, predominantly on the left side of an animal. The mean number of labelled cells per animal was eighty-seven, of which the majority was in the T10-T13 spinal ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)

Transganglionic transport of horseradish peroxidase (HRP) has been used to study the anatomy of the central projection of somatic and visceral afferent fibers to the thoracic spinal cord of the cat. A dense concentration of somatic afferent fibers and terminals was found in laminae I and II of the dorsal horn and more scattered terminals were present in laminae III, IV and V and in Clarke's column. In contrast, visceral afferent fibers and terminals were found only in lamina I or reaching lamina V via a small bundle of fibers located in the lateral border of the dorsal horn. These results indicate that fine afferent fibers from viscera, unlike those of cutaneous origin, do not project to the substantia gelatinosa (lamina II) of the dorsal horn.

Single unit electrical activity has been recorded extracellularly from 103 neurones in the thoracic spinal cord of decerebrate cats. The responses of these neurons to electrical stimulation of cutaneous and visceral afferent fibres, their projection through ascending sensory pathways and the effects of descending impulses on the neurones have been studied. Of the 103 neurones recorded, 45 (43.7%) responded only to activation of cutaneous afferent fibres (‘Somatic’ neurones). Their recording sites were located mainly in laminae II, III and IV of the dorsal horn. The remaining 58 neurones (56.3%) responded to stimulation of cutaneous and visceral afferent fibres (‘Viscero-somatic’ neurones). Their recording sites were located in laminae I, V, VII and VIII of the grey matter. Sixteen neurones had axons projecting through ascending pathways: 6 were post-synaptic dorsal column cells (PSDC), 2 were spino-cervical tract cells (SCT), 5 projected through the contralateral ventro-lateral funiculus (VLQ) and 3 through the ipsilateral dorso-lateral funiculus (DLF). All PSDC cells were somatic and all VLQ neurones were viscero-somatic. Reversible spinalization of the animals by cold block resulted in a selective increase of the responses of viscero-somatic neurones to cutaneous and visceral C-fibre input. In some viscero-somatic neurones, cold block induced a reduction or abolition of the visceral input suggesting its mediation via supraspinal loops. Electrical stimulation of the ipsilateral DLF evoked non-specific inhibitions of all inputs to viscero-somatic neurones. These results are discussed in relation with the mechanisms of visceral sensation.

It has been suggested that sampling of rectal contents by the anal canal may play a role in the continence mechanism. To investigate this concept we studied 18 patients with faecal incontinence and 18 age and sex matched controls. A microtransducer catheter was positioned so that pressures were recorded from the rectum, the junction of the upper and middle thirds of the anal canal and the lower anal canal. Recordings were taken at rest and while distending the rectum with air in a balloon, and then with air injected freely into the rectum. Sampling (equalization of the rectal and upper anal canal pressures) was seen to occur spontaneously in 16 of the controls and only 6 of the incontinent group (P