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1. Recordings were made from gastrocnemius medialis (GM), semitendinosus (ST) and tibialis anterior/extensor digitorum longus (TA/EDL) motor nerves during mechanical and electrical stimulation of the skin of the foot in decerebrated and spinalized rabbits. 2. GM motoneurones were excited from the heel and not from the toes, whereas TA/EDL responded to stimulation at the toes but not at the heel. ST also responded to electrical and mechanical stimulation at the toes, but there was a disparity between the effects of the two types of stimuli when they were applied at the heel: ST motoneurones fired in response to electrical stimulation of the heel but showed only an 'off' response to mechanical stimulation at this site. 3. The opioid antagonist naloxone caused a dose-dependent increase in all reflexes evoked by electrical stimulation of the skin. The heel-GM, toes-ST and toes-TA/EDL reflexes all increased to more than 3 times control levels with naloxone, which also caused significant decreases in the latencies of these reflex responses. On the other hand, the heel-ST response increased to just 1.4 times control levels and showed no decrease in latency with the opioid antagonist. 4. These data suggest that segmental withdrawal reflex pathways in the rabbit are suppressed by endogenous opioid peptides. This opioid-mediated inhibition seems to operate non-selectively on reflex pathways between cutaneous afferents and motoneurones.

We present a series of 2305 previously untreated histologically proven squamous carcinomas of the mucosal surfaces of the upper aerodigestive tract managed by one of us in a 27-year period. 62 (2.7%) of the patients were aged 40 years or younger. The sex ratio between young and old patients was similar but, as expected, the younger patients were in better physical condition. Furthermore, 90% of young patients were treated, compared with only 78% of the older patients. Younger patients had a higher incidence of oropharyngeal tumours and lymph node metastases, but the proportion of poorly differentiated tumours, and stage T3-T4 tumours, was similar, as was the metastatic rate. The crude survival of the younger patients was 10% better than that of the older group, and adjusted (life-table) survival was 9% better, and this better survival in younger patients was significant when differing site incidence and N-stage were allowed for by multivariate analysis. The recurrence rate at the primary site was 19% in the younger patients and 15% in older patients, but this difference was not significant. The recurrence rate in cervical lymph nodes was similar in both age groups: 37% at 2 years in young patients and 38% in older patients.

The sural-gastrocnemius reflex was observed in decerebrated rabbits during intrathecal application of four alpha-adrenoceptor antagonists. Idazoxan and yohimbine, which are antagonists at the alpha 2-receptor, caused facilitation of the reflex, although idazoxan was more potent and produced a larger overall increase in the reflex response. However, when given after yohimbine, idazoxan elicited no further increase in reflex responses. The differences between the two drugs may result from the interaction of yohimbine with receptors for 5-hydroxytryptamine. The selective alpha 1-receptor antagonist prazosin had no consistent effects when given alone, but reduced the facilitatory effects of idazoxan. The putative selective post-junctional alpha 2-receptor blocker SK&F 104078 had no significant effects when given alone, nor did it influence the facilitatory action of a subsequent dose of idazoxan. Section of the spinal cord in the presence of idazoxan always caused a decrease in gastrocnemius responses to sural nerve stimulation. These data show that the facilitatory effects of idazoxan are almost certainly mediated at the spinal cord and that they do not involve blockade of alpha 1-receptors. It appears that idazoxan acts by blockade of adrenergic descending inhibition in combination with increased descending facilitation. The inhibition is probably mediated through noradrenaline acting at alpha 2-receptors, and the facilitation may be the result of release of noradrenaline (acting at alpha 1-receptors) and 5-hydroxytryptamine in the spinal cord.

1. In decerebrated rabbits, repetitive stimulation of the high-threshold afferents of the left common peroneal (CP) nerve evokes prolonged depression of the sural-gastrocnemius medialis (GM) reflex recorded in the same limb. This inhibition is antagonized by co-administration of the opioid antagonist naloxone with the alpha 2-adrenoceptor antagonist idazoxan. The present study was designed to investigate whether such inhibition could be elicited from the contralateral hindlimb or the forelimbs. 2. The sural-GM reflex of decerebrated rabbits was depressed for more than 15 min after stimulation of either ipsilateral or contralateral common peroneal (CP) or median nerves with 500 pulses of 20 V, 1 ms given at 5 Hz. The order of efficacy for generating this inhibition was ipsilateral CP greater than contralateral CP greater than or equal to ipsilateral median = contralateral median. In three of thirty-nine rabbits, stimulation of the median nerves caused facilitation of the sural-GM reflex. 3. Idazoxan (1-2 mg/kg I.V.) did not significantly alter the depressant effect of ipsilateral CP stimulation but reduced that evoked by either median nerve and almost abolished the inhibition evoked from the contralateral CP nerve. 4. Naloxone (0.25 mg/kg I.V.) reduced the effects of ipsilateral CP stimulation, did not alter the inhibition evoked from contralateral CP, and had equivocal actions on the responses to median nerve stimulation. 5. When given together, the two antagonists almost abolished the effects of stimulating the median nerves and the contralateral CP nerve, and markedly reduced the inhibition evoked from the ipsilateral CP nerve. 6. These data show that prolonged inhibition of the sural-GM reflex can be evoked by stimulation of nerves in all four limbs and that in each case the inhibition can be blocked or reduced by co-administration of antagonists to opioid and alpha 2-adrenergic receptors. Such persistent inhibition of reflexes may serve to inhibit withdrawal reflexes in situations where interruptions to normal movement would be disadvantageous.

Antibody microprobes were used to study the release of immunoreactive neurokinin A into the spinal cord of anaesthetised cats during and following injection of a knee joint with kaolin and carrageenan. A basal level of immunoreactive neurokinin A was detected prior to any noxious stimuli. Innocuous mechanical joint stimuli (flexion or pressure) did not alter this basal level of release. However, on injection of kaolin and carrageenan into a knee joint, evidence of release into the ipsilateral spinal cord was immediately observed. Initially, immunoreactive neurokinin A was detected in 2 regions: one at the dorsal surface of the spinal cord and the other centred on the superficial dorsal horn. Within 1 h of joint injection, however, immunoreactive neurokinin A was detected throughout the dorsal horn and the adjacent white matter. The extensive spread and persistence of immunoreactive neurokinin A in the spinal cord may underlie some of the prolonged excitability changes evoked by brief noxious stimuli and peripheral inflammation reported by other laboratories.

Repetitive stimulation of the small myelinated and non-myelinated afferents of the common peroneal (c.p.) nerve evokes a long-lasting (20-25 min), naloxone-reversible inhibition of the sural-gastrocnemius reflex in the decerebrated and spinalized rabbit. Altering the number and frequency of stimuli applied to the c.p. nerve showed that this inhibition was dependent on temporal summation of afferent input from that nerve, and that the optimum frequency for producing the effect was between 2 and 10 Hz. Application of natural conditioning stimuli in and around the receptive field of the c.p. nerve showed that noxious, but not innocuous, mechanical and thermal stimuli could evoke long-lasting inhibition of the sural-gastrocnemius reflex. Thermal stimuli produced a biphasic change in the excitability of the reflex with facilitation followed by inhibition. The opioid antagonist naloxone (250 micrograms.kg-1) blocked all suppression resulting from these natural noxious stimuli. Chemical stimulation of the skin with mustard oil did not evoke naloxone-reversible inhibition of the reflex. These results indicate that intensely noxious stimuli can promote the release of opioid peptides in the spinal cord, and that one of the functions of these peptides may be to regulate the level of excitability in withdrawal reflex pathways.

Electrical stimuli were applied to tooth-pulp in cats and the thresholds of the jaw-opening reflex and of neurons in the trigeminal sensory nuclei were determined. The effects of the method of preparation of the animal for stereotaxic recording were determined by making observations on animals set up in one of three ways: acutely in the usual manner; chronically, three to five days before recording; and acutely with precautions to minimize nociceptive input to the central nervous system. The threshold of the jaw-opening reflex increased progressively during the setting up of the normal, acute preparations and at the time brainstem recording began was significantly higher in these than in either the chronic or low-trauma acute preparations. Previous studies have shown that the increase in threshold is maintained for several hours and is not due to the effects of the anaesthetic. In normal acute preparations, few units (27/154) were found that had thresholds below 50 microA, 0.1 ms, whereas many units were encountered that responded to such a stimulus in chronic (147/152) and low-trauma acute (99/127) animals. In the chronic and in low-trauma acute preparations, there was no significant difference between the thresholds of the units in the main sensory trigeminal nucleus and spinal subnucleus oralis compared with those in subnucleus caudalis. Thus the preparation of an animal for stereotaxic recording can cause a severe and long-lasting depression in the excitability of neurons in the trigeminal sensory nuclei and an increase in the threshold of the jaw-opening reflex. This effect will have influenced the results of previous studies on the responses evoked in central neurons by stimulation of tooth-pulp, and may have similarly affected recordings from other regions.

The effects of intravenous morphine, (-)-naloxone and (+)-naloxone have been studied on three ipsilateral cutaneo-muscular reflexes in spinal rabbits. Morphine, 3 mg/kg caused a slow-onset depression of all three reflexes. This effect was naloxone reversible. The ipsilateral extensor reflexes, sural to gastrocnemius medialis and saphenous to vastus lateralis were both enhanced to more than double control size following a 5 micrograms/kg dose of naloxone given in the absence of morphine. For the sural-gastrocnemius reflex, naloxone potentiated the reflex drive from all groups of myelinated afferent fibres. The ipsilateral flexion reflex, sural to semitendinosus, was only weakly enhanced by naloxone, the 5 micrograms dose leading to an increase in the size of the reflex to 130% of control. All observed actions of naloxone were stereospecific as the enantiomer (+)-naloxone failed to affect any of the reflexes even in a dose of 50 micrograms/kg. We conclude from these findings that opioid peptides are tonically released in rabbit spinal cord, and that they have differential effects in control of flexion and extension reflexes. It is suggested that the ipsilateral extension reflexes are held under a more powerful opioid-mediated depression than that operating upon the flexion reflexes, and that this difference may be related to the greater inhibitory inflow to extensor motoneurones from ipsilateral skin areas.

In spinally transected, decerebrated rabbits, the reflex evoked in the ankle extensor gastrocnemius medialis by stimulation of the ipsilateral sural nerve was depressed for periods of 12-45 min following tetanic stimulation of the high-threshold afferents of the ipsilateral tibial, common peroneal, gastrocnemius medialis and sural nerves. It was unaffected by similar tetanic stimulation of ipsilateral saphenous or semitendinosus nerves, or of any nerve in the contralateral limb. The extension reflex between saphenous nerve and vastus lateralis was depressed after tetanic stimulation of saphenous nerve. Post-tetanic depression was partially reversed by the opioid antagonist (-)-naloxone in a dose of 50 micrograms/kg I.V., implicating the involvement of endogenous opioids. The sural-semitendinosus flexion reflex was depressed only by stimulation of the homonymous muscle nerve. It was enhanced for up to 20 min after iterative stimulation of the high-threshold fibres of the ipsilateral sural nerve. This reflex was unaffected by tetanic stimulation of any of the other ipsilateral or contralateral nerves tested. Tetanic stimulation of high-threshold afferents of hind-limb nerves apparently stimulates the release of endogenous opioids within the spinal cord. It is proposed that this is brought about by the activation of enkephalin-containing neurones in the superficial laminae of the dorsal horn.

Spinal reflexes in the rabbit are suppressed tonically by endogenous opioids. The contributions made to this suppression by mu-, delta- and kappa-opioid receptors have been investigated by studying the actions of a range of opioid antagonists and agonists on reflexes evoked by sural nerve stimulation in the ankle extensor gastrocnemius medialis (g.m.), and in the knee flexor semitendinosus (s.t.). When given at a total dose of 88.5 micrograms kg-1 i.v., either of the universal opioid receptor antagonists (-)-naloxone and (-)-quadazocine enhanced the g.m. response to more than 7 times the pre-drug control values, and the s.t. reflex to 1.5 times controls. The effects of quadazocine were stereospecific. The selective delta antagonist ICI 174864 (3.5 mg kg-1 i.v. total) also augmented the g.m. reflex but only to twice pre-drug controls. The mu-agonists fentanyl (100 micrograms kg-1) and morphine (50 mg kg-1) suppressed both g.m. and s.t. reflex responses to less than half control levels by a naloxone-reversible mechanism. The kappa-agonists bremazocine (50 micrograms kg-1 total), tifluadom (100 micrograms kg-1), ethylketocyclazocine (200 micrograms kg-1) and U50488H (1 mg kg-1) potentiated the g.m. reflex and had variable effects on the s.t. response. Naloxone usually added to the facilitatory actions of these drugs. kappa-Opioid receptor agonists also caused a profound, naloxone-reversible depression of arterial blood pressure. It may be concluded that the endogenous opioid-mediated suppression of spinal reflexes in the rabbit is mediated mainly, if not exclusively, through mu-receptors. There are no known endogenous ligands which are specific for the mu-receptor, so in the present case it seems that selectivity is determined by the receptor population rather than by the ligand.

In a 2-month prospective study of streptococci isolated from urine specimens in the laboratory, 242 strains of catalase-negative gram-positive cocci or coccobacilli were isolated in substantial numbers from 11,725 specimens. These comprised 10% of the important isolates. Species identification of all isolates was undertaken. 74 (30%) of the isolates were of species other than Streptococcus faecalis and S agalactiae. 79 (33%) were not detected on cysteine-lactose-electrolyte-deficient agar after overnight incubation in a carbon dioxide incubator. 20 of the 24 isolates of coccobacilli were Gardnerella vaginalis. Many of the isolates of fastidious species were accompanied by pyuria. An isolation protocol practicable in busy laboratories is proposed.

1. In the decerebrated and spinalized rabbit, electrical stimulation of the sural nerve evokes a short-latency reflex in the ipsilateral ankle extensor gastrocnemius medialis (GM) which is tonically suppressed by endogenous opioids. In the present study we have investigated the inhibitory influences affecting this reflex in non-spinalized, decerebrated rabbits. 2. In non-spinalized rabbits, the thresholds and latencies of the sural-GM reflex were significantly higher than in spinalized preparations. The opioid antagonist naloxone and the alpha-adrenoceptor antagonist idazoxan potentiated the reflex in both preparations. Naloxone was significantly more effective in spinalized rabbits whereas idazoxan had a much larger effect in non-spinalized animals. 3. When the spinal cord was sectioned in the presence of naloxone alone, the GM reflex always increased in size. An ipsilateral hemisection of the cord was as effective as total section in this respect. When the section was performed in the presence of idazoxan and naloxone, the response usually decreased in size. 4. The alpha 2-adrenoceptor agonist clonidine depressed the reflex in spinalized rabbits, an action that was reversed by idazoxan but not by naloxone. 5. These data show that in the decerebrated, non-spinalized rabbit, the sural-GM reflex is tonically suppressed by endogenous opioids, presumably acting at the segmental level, and by an ipsilateral descending pathway which involves an alpha-adrenoceptor-mediated synapse. Activity in this descending pathway masks the facilitatory effects of opioid antagonists on spinal reflexes in this preparation.

Selective electrical stimulation of the non-myelinated C fibres of the sural nerve in the decerebrated, spinalized rabbit evoked long-latency (76-160 ms), long-lasting (greater than 100 ms) reflex responses in the ipsilateral ankle extensor gastrocnemius medialis (GM). Activation of the same fibres elicited little or no response from the ipsilateral knee flexor semitendinosus (ST). Reflex responses were evoked in both GM and ST muscle nerves by stimulation of the A beta afferents of the sural nerve. The A beta-elicited reflex in GM was enhanced, and that in ST depressed by prior activation of sural nerve C fibres. Strychnine, but not picrotoxin or mecamylamine, blocked C fibre-induced inhibition of the flexor reflex. Pinching the heel with serrated forceps produced an immediate reflex discharge in GM motoneurones, whereas ST responded upon termination of the stimulus. Pinching the second toe evoked reflex activity in ST but not in GM. After strychnine (0.5 mg kg-1), both sets of motoneurones responded simultaneously to stimulation of either the heel or the toe. These data show that sural and other afferent fibres from the heel excite ipsilateral GM motoneurones and inhibit ST reflex responses. One interpretation of these findings is that fine sural afferents activate parallel inhibitory and excitatory pathways, of which the former is sensitive to strychnine and therefore probably mediated by glycine.

The bradycardia evoked by electrical stimulation of the peripheral cut end of the rabbit vagus nerve is mediated by both myelinated and non-myelinated fibres. The purpose of this study was to assess the effects of non-myelinated fibres on heart rate in the rabbit using selective electrical stimulation techniques. In 8 rabbits selective activation of non-myelinated fibres using reversed polarity triangular shaped pulses (10 Hz, 20 s), resulted in a slowly developing fall in heart rate of 24.1 +/- 1.1 beats/min which outlasted the period of stimulation by 58.4 +/- 4.2 s. In 4 rabbits stimulation of myelinated fibres at 10 Hz for 20 s resulted in a fall in heart rate of 24.5 +/- 2.6 beats/min. On stimulation of both myelinated and non-myelinated fibres heart rate fell by 39.9 +/- 3.2 beats/min. Heart rate returned rapidly to control value following stimulation of myelinated fibres (5.6 +/- 0.5 s) but only slowly after stimulation of both myelinated and non-myelinated fibres (56.7 +/- 4.9 s). Atropine (5 mg/kg, i.v.) abolished all effects of vagal stimulation on heart rate. Hexamethonium (15 mg/kg, i.v.) abolished the effect of myelinated fibres on heart rate but did not affect the fall in heart rate produced by non-myelinated fibres. We suggest that the prolonged effects on stimulation of non-myelinated fibres may reflect the persistent action of a non-cholinergic excitatory transmitter at the cardiac parasympathetic ganglia.

Electrical stimulation of the sural nerve of the rabbit evokes reflexes in the ipsilateral ankle extensor gastrocnemius medialis and in the knee flexor semitendinosus which are differentially modulated by endogenous opioids. Intravenous injection of the putative functional opioid antagonist, thyrotropin releasing hormone (TRH) or its analogue RX77368, caused the extensor response to double in size and the flexor reflex to increase to 1.5-1.7 times pre-drug controls. The opioid RX77368 had no effect on the naloxone-reversible inhibition of the gastrocnemius reflex which followed tetanic stimulation of the fine afferent fibres of the common peroneal or sural nerves. The cholecystokinin antagonist proglumide, which has been shown to enhance the actions of endogenous opioids in some species, had no effects on either reflex. It is possible that TRH acts as an excitatory neurotransmitter or modulator in the spinal cord of the rabbit opposing, but not blocking, the actions of endogenous opioids.

The effects on the jaw-opening reflex evoked by tooth-pulp stimulation of surgical trauma, decerebration and the destruction of a number of nuclei associated with descending inhibition of trigeminal or spinal neurones have been investigated in the cat. Surgical preparation caused a progressive elevation of the digastric reflex threshold. After decerebration, reflex thresholds remained elevated for 8-11 h before returning to close to pre-surgical control values. Destruction of the nucleus raphe magnus and of the periaqueductal grey matter did not affect the depressed reflex in decerebrate or anaesthetized cats. Variable effects were produced by bilateral ablation of the juxta-raphe reticular formation and destruction of the rostral ipsilateral lateral reticular formation of the brainstem.

Previous studies indicate that the threshold of the jaw opening reflex (JOR) evoked by tooth-pulp stimulation is much lower in cats subjected to minimal surgical trauma and a short period of anaesthesia than in animals prepared for stereotaxic recording from the brainstem. Experiments have been carried out to determine whether the higher JOR thresholds observed in the latter group of cats could be attributed to the duration of the anaesthesia or the greater surgical trauma to which they were subjected. The effects on the JOR evoked by tooth-pulp stimulation of brief episodes of noxious and high intensity electrical stimulation of other tissues have been studied in anaesthetized cats. In lightly anaesthetized, control animals, the reflex threshold was usually below 100 microA, 0.1 ms and maintained anaesthesia did not affect this. Alphaxalone/alphadolone, methohexitone and alpha-chloralose produced similar results. Noxious or high intensity electrical stimuli applied to a paw, a pinna or the scalp caused either no change or a decrease in the JOR threshold of cats lightly anaesthetized with alphaxalone/alphadolone. With deeper anaesthesia, these same conditioning stimuli caused a maintained increase in JOR threshold which could be reversed by decreasing the anaesthetic dose. The results suggest that the high threshold of the JOR observed in earlier experiments was not due to anaesthesia but may have been caused by trauma.

The short-latency sural to gastrocnemius reflex in the decerebrated rabbit was depressed for 20-30 min following high intensity conditioning stimulation of the common peroneal nerve. This effect was observed in animals with or without spinal section, but was greater in non-spinalized preparations. Graded conditioning stimuli showed that it was necessary to activate fine myelinated common peroneal axons to inhibit the reflex. In spinalized rabbits, maximal inhibition was achieved with conditioning stimulation of fine myelinated axons and was completely reversed by the opioid antagonist naloxone. In non-spinalized rabbits, maximal inhibition was only obtained with conditioning stimuli which activated non-myelinated axons. In these preparations the effects of common peroneal nerve stimuli were only blocked by co-administration of naloxone with the alpha 2-adrenoceptor antagonist idazoxan. Thus high intensity peripheral nerve stimuli activated a segmental opioidergic and a supraspinal adrenergic suppression of the sural-gastrocnemius withdrawal reflex. Such long-lasting suppression of reflex excitability may contribute to recovery from intensely noxious stimuli.