Intracerebroventricular self-injection of morphine in response to pain in the rat

Rats were chronically implanted with a lateral cerebral ventricular guide cannula. After recovery they were trained to self-inject morphine sulfate. A week after this training period, self-injection behavior was studied during nociceptive stimulation. In response to a nociceptive stimulation rats increased their intracerebroventricular self-administration of morphine. This effect is specific for morphine since under identical conditions rats did not increase NaCl administration. Naloxone pretreatment inhibits self-administration of morphine in 5 rats. However, two rats increased morphine self-intake. These results show that rats can directly perceive a decrease of pain sensation induced by the morphine self-administration. This experimental situation is therefore similar to the therapeutic situation in humans, in which the criterion of efficacy of an analgesic is a reduction of the conscious pain sensation. Experimental self-administration during painful stimulation might therefore be used for preclinical evaluation of the efficacy of an analgesic drug.     

The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain

The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of spinal versus systemic administration of morphine on the natural and electrically evoked responses of spinal neurones of rats with a selective spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In spinal nerve ligated rats, morphine (0.1-5 microg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1-6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.     

Nociceptive input from the rat thoracolumbar fascia to lumbar dorsal horn neurones

In anaesthetised rats, systematic electrophysiological recordings from dorsal horn neurones in spinal segments Th13–L5 were made to obtain information about the spinal nociceptive processing from the lumbar thoracolumbar fascia. Six to fourteen percent of the neurones in the spinal segments Th13–L2 had nociceptive input from the thoracolumbar fascia in naïve animals, no neurones responsive to input from the lumbar fascia were found in segments L3–L5. The segmental location of the receptive fields in the fascia was shifted 2–4 segments caudally relative to the spinal segment recorded from. Most neurones were convergent in that they received additional input from other deep somatic tissues in the low back (87%) and from the skin in the abdominal wall or the proximal leg (50%). The proportion of neurones responsive to input from the thoracolumbar fascia rose significantly from 4% to 15% (P < 0.05) in animals with an experimentally-induced inflammation of a low back muscle (multifidus). Moreover, neurones in spinal segment L3 – that did not receive input from the fascia in normal animals – responded to fascia input in animals with inflamed muscle. The data suggest that the nociceptive input from the thoracolumbar fascia contributes to the pain in low back pain patients.     

Hypothalamic inhibition of rat dorsal horn neuronal responses to noxious skin heating

The responses of single lumbar dorsal horn neurons to noxious radiant heat stimuli (42-54 degrees C, 10 sec, 1/2 min) applied to glabrous hind paw skin were recorded in rats anesthetized with sodium pentobarbital. Unit responses to 50 or 52 degrees C stimuli were constant over time and were consistently and powerfully inhibited during bipolar stimulation (three 100 msec trains/sec at 100 Hz, 200 microA) in the medial hypothalamus. Inhibition was also evoked by stimulation in medial and ventrobasal thalamic nuclei, lateral hypothalamus and adjacent cerebral peduncle, and amygdala. Inhibition increased with graded increases in intensity of hypothalamic stimulation, with a mean inhibitory threshold of 71 +/- 43 (S.D.) microA for 13 units. The responses of dorsal horn units to graded increases in the temperature of noxious heat stimuli were inhibited during hypothalamic stimulation, such that slopes of the linear temperature-response functions were reduced with no change in response threshold (mean: approximately 44 degrees C). Inhibition was blocked or reduced in 4/7 units following systemic administration of the 5-hydroxytryptamine (5-HT) antagonist methysergide. The results confirm and extend previous work in the cat and are discussed in relation to analgesic mechanisms.     

鞘内注射吗啡对坐骨神经慢性压迫性损伤大鼠腰段脊髓后角神经元中c-fos蛋白表达的影响

目的 坐骨神经慢性压迫性损伤(CCI)可以引起腰段脊髓后角中c-fos的表达.μ-阿片受体长期以来被认为与脊髓中的镇痛机制有关,而吗啡作为μ-阿片受体激动剂被应用于病理性疼痛的治疗中.本实验通过给坐骨神经CCI大鼠模型鞘内注射吗啡,观察其对脊髓后角中c-fos表达的影响.方法 23只Sprague-Dawley大鼠随机分为三组.其中B、C两组大鼠接受右侧坐骨神经外周结扎手术,而A组为假手术组.9 d后,A、C两组大鼠接受鞘内注射吗啡同时给B组大鼠鞘内注射生理盐水.注射后6 d,解剖三组大鼠并取出L3～L5节段的脊髓制成40μm的冰冻切片.标本在室温下进行荧光免疫染色后制成玻片.使用激光共焦点显微镜下观察各脊髓切片标本双侧c-fos的染色情况.结果 三组大鼠手术侧同侧的脊髓后角中c-fos阳性神经元较对侧明显增多.但是c组大鼠脊髓后角同侧的c-fos阳性神经元较B组少.结论 μ-阿片受体激动剂能明显减少CCI大鼠腰段脊髓后角中c-fos的表达.     

Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn

We have studied the effects of intrathecal morphine on the responses of 38 dorsal horn neurones in the intact rat under halothane anaesthesia to A and C fibre electrical stimulation and to natural stimuli applied to their receptive fields. Morphine selectively reduced the C fibre and pinch evoked activity in a dose-dependent naloxone-reversible manner with an ED50 of 7 nmoles. The 'wind-up' of neurones to repetitive stimulation was little altered except with the highest doses (50-150 nmoles) tested. By contrast, the A fibre evoked responses of the neurones were only slightly reduced by morphine and both the tactile responses and receptive field size to innocuous stimuli enhanced for certain cells. The results are discussed in relation to the spinal actions of opiates and their clinical applications.     

Benzodiazepines and pain: effects of midazolam on the activities of nociceptive non-specific dorsal horn neurons in the rat spinal cord.

The high density of GABA-benzodiazepine receptors in the superficial dorsal horn suggests a possible involvement of benzodiazepines (BZs) in the modulation of spinal pain processes. In this electrophysiological study we have examined the effects of midazolam (MZ), a water-soluble short-acting BZ, on the activities of 57 nociceptive non-specific dorsal horn cells, one in each animal. Recordings were performed at lumbar level in unanesthetized decerebrate spinal rats before and following intravenous injection of MZ (1, 2 or 5 mg/kg). The spontaneous activity was weakly and significantly but not dose dependently reduced by MZ. For the total neuronal population MZ induced no significant effect on C-fiber evoked responses, whatever the dose used. More precise analysis shows that for 45/55 neurons the responses were slightly depressed, but this effect was not dose dependent. In contrast, A delta-fiber evoked responses were markedly and dose dependently depressed. These effects of MZ were reversed by intravenous administration of the antagonist flumazenil (FZ). Despite the fact that MZ displays a very weak effect on responses due to C-fiber stimulation, the possible involvement of BZs in the modulation of nociceptive transmission at the level of the dorsal horn is discussed on the basis of clinical and experimental findings, taking into account the role of GABAergic mechanisms in sensory events.     

Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain

Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses of superficial and deep dorsal horn neurones in halothane-anaesthetized rats. Receptive field size was significantly enlarged for superficial neurones in the MRMT-1 animals. Superficial cells were characterised as either nociceptive specific (NS) or wide dynamic range (WDR). The ratio of WDR to NS cells was substantially different between sham operated (growth media alone) (26:74%) and MRMT-1 injected rats (47:53%). NS cells showed no significant difference in their neuronal responses in MRMT-1-injected compared to sham rats. However, superficial WDR neurones in MRMT-1-injected rats had significantly increased responses to mechanical, thermal and electrical (A beta-, C fibre-, and post-discharge evoked response) stimuli. Deep WDR neurones showed less pronounced changes to the superficial dorsal horn, however, the response to thermal and electrical stimuli, but not mechanical, were significantly increased in the MRMT-1-injected rats. In conclusion, the spinal cord is significantly hyperexcitable with previously superficial NS cells becoming responsive to wide-dynamic range stimuli possibly driving this plasticity via ascending and descending facilitatory pathways. The alterations in superficial dorsal horn neurones have not been reported in neuropathy or inflammation adding to the evidence for cancer-induced bone pain reflecting a unique pain state.     

Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy

The mechanisms underlying the relief of neuropathic pain of peripheral origin by spinal cord stimulation (SCS) are poorly understood. The present study was designed to investigate the effects of SCS on evoked and spontaneous discharges in dorsal horn neurons in intact and in nerve-injured rats subjected to partial sciatic nerve ligation according to Seltzer et al. (1990). Tactile sensitivity in the hind paw was assessed in behavioral tests using von Frey filaments. The presence of 'allodynia' was defined as a withdrawal response to a filament of 10 g or less. Under halothane/oxygen anesthesia the effects of SCS (50 Hz, 0.2 ms, 80-620 microA, 5 min.) on mechanically evoked (brush and innocuous press on the hind paw) responses and spontaneous discharges were investigated in wide-dynamic range (WDR) neurons in three groups of animals: (1) rats that displayed 'allodynia' after nerve ligation (2) rats without signs of 'allodynia' after surgery and (3) control, intact rats. A significantly increased frequency of spontaneous discharge and of responsiveness to brush and press was found in the group of allodynic, as compared with non-allodynic and control rats. The majority (63%) of the investigated neurons in these animals displayed afterdischarge in response to press stimulation. SCS induced a significant depression of both the principal response and the afterdischarge in allodynic rats: the discharge during brush stimulation was reduced to 86 +/- 8.2% and during press to 77.4 +/- 4.5% as compared with the prestimulation value. These depressive effects on evoked responses in allodynic rats outlasted SCS by 10.5 +/- 1.7 min during which time the responses gradually recovered. The frequency of spontaneous discharge was markedly decreased in approximately one third of the neurons, whereas in another third it was increased. In non-allodynic and control rats, SCS had no significant depressive effects on the evoked responses and spontaneous discharge. The results suggest that SCS may provide a suppressive action on dorsal horn neuronal hyperexcitability associated with signs of peripheral neuropathy. The suppressive effect of SCS on tactile allodynia, as previously observed in behavioral experiments, presumably corresponds to a normalization of the excitability of WDR cells in response to innocuous stimuli.     

Intravenous morphine does not modify dorsal horn touch-evoked allodynia in the mononeuropathic rat: a Fos study

In a model of mononeuropathic pain (chronic constriction injury of the sciatic nerve, CCI), we have demonstrated that light touch stimuli (stroking) to the paw induced Fos-like immunoreactivity (Fos-LI) in the superficial and deep dorsal horn of the rat spinal cord (Catheline et al., Pain 80 (1999a) 347). The efficacy of opioids in neuropathic pain being controversial, we have tested the effects of morphine (0.3, 1 and 3 mg/kg intravenous, i.v.) on this spinal Fos-LI evoked by light tactile stimuli, which could be related to mechanical allodynia. Morphine did not change the level of spinal Fos-LI observed following light touch stimuli in the CCI rats (43 +/- 3, 38 +/- 7, and 37 +/- 4 Fos-LI neurones/40 microm L4-L5 section, respectively, for the three doses versus 32 +/- 4 in the control group). In contrast, the administration of 3 mg/kg of i.v. morphine reduced by 30% the number of Fos-LI neurones induced by heat stimulation (52 degrees C, 15 s duration) in CCI rats (P < 0.05) as in sham-operated rats. These effects were reversed by the systemic administration of naloxone. The lack of effect of morphine on touch-evoked Fos-LI in the superficial dorsal horn reinforces the assertion that dynamic mechanical allodynia is related to information transmitted by A-beta fibres, since opioid receptors are mainly located on thin primary afferent fibres. Our results provide a basis for a certain form of allodynia that is insensitive to morphine.     

Inhibition of nociceptive neuronal responses in the cat's spinal dorsal horn by electrical stimulation and morphine microinjection in nucleus raphe magnus

The descending inhibitions produced by morphine microinjection and electrical stimulation in the nucleus raphe magnus (NRM) on dorsal horn neurons excited by noxious heating of the skin and/or electrical stimulation of hind limb nerves were examined in the cat. The responses to A-volleys were inhibited to 60.1% (mean, n = 9), those to C-volleys to 64.8% of control (mean, n = 6) and responses to skin heating to 25.3% (mean, n = 8) by electrical NRM stimulation. Morphine (e.g., 10 or 20 micrograms) microinjected into the NRM markedly reduced the responses elicited by afferent C-fiber stimulation (mean 55.6%, n = 8) and the responses to noxious skin heating (mean 38.1%, n = 8), while responses to A-volleys in hind limb nerves were less attenuated (mean 73.6%, n = 8). The effects of morphine were partially or completely blocked by microinjection (10 micrograms) of naloxone into the NRM. It is concluded that morphine microinjection into the NRM generates descending inhibition on the transmission of nociceptive information in the dorsal horn of the spinal cord. This may partly explain the mechanisms of morphine analgesia.     

Nociceptor-driven dorsal horn neurones in the lumbar spinal cord of the cat

Single dorsal horn neurones have been recorded extracellularly in the lumbar spinal cord of cats anaesthetized with chloralose. Cold block at L₁ was used to provide reversible spinalization. The location of the units in the dorsal horn was marked by the electrophoretic deposition of pontamine sky blue from the recording microelectrode. There was a clear somatotopic representation of the ventrolateral surface of the foot in the L₆ segment. Thirty-five of the 46 units recorded in the marginal zone of the L₆ dorsal horn (lamina I) could only be excited by volleys in small afferent fibres and by noxious stimulation of the skin in the foot regions and were termed class 3 cells. The remaining 11 units could, in addition, be excited by sensitive cutaneous mechanosensitive afferent units — they were class 2 units. The ‘specific’ nociceptor-driven neurones could be divided into 2 subclasses on the basis of their excitability by afferent fibres. Class 3 (a) were excited only by Aδ cutaneous afferents and class 3 (b) by both Aδ and C cutaneous afferents. Some of the latter were also excited by Aδ and C afferent fibres in the lateral gastrocnemius nerve. When tested by natural stimulation all class 3 cells were excited by noxious mechanical stimuli, but only the 3 (b) units were effectively excited by heating the skin. This discharge in 3 (b) units could be suppressed by electrical stimulation of large (group II) cutaneous myelinated afferent fibres and a similar effect could be produced in responses evoked by Aδ and C afferent volleys. Additional inhibition was accomplished by electrical stimulation of the slower myelinated cutaneous (Aδ or group III) afferent fibres. The excitability of the class 3 cells was greater in spinal preparations but the tonic descending inhibition was weaker than the apparently similar descending tonic inhibition of class 2 cells. The results are discussed with reference to pain mechanisms.     

Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.     

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.     

Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn

We investigated the effects of gabapentin (GBP) on glutamatergic synaptic transmission in the dorsal horn of the rat spinal cord. Patch clamp whole cell recordings were made from superficial and deep dorsal horn neurons of rat spinal cord slices. In the majority of neurons in the superficial lamina, GBP decreased the amplitudes of evoked excitatory postsynaptic currents (evoked EPSCs) mediated by either non-NMDA or NMDA receptors. In contrast, neurons in the deep lamina showed variable effects, with a lower incidence of decrease in amplitude of evoked EPSCs and a subset of neurons showing an increase in amplitude of evoked NMDA receptor-mediated EPSCs. No enhancement of evoked non-NMDA receptor-mediated EPSCs was observed in either lamina. To determine whether the observed effects of GBP are presynaptic and/or postsynaptic, spontaneous miniature excitatory postsynaptic currents (mEPSCs) were studied. In neurons that showed a decrease in its frequency of mEPSCs by GBP, no change in the amplitude or shape accompanied the effect. On the other hand, in neurons that showed an increase in the frequency of NMDA receptor-mediated mEPSCs, the effect accompanied an increase in amplitude. These results suggest that GBP presynaptically inhibits glutamatergic synaptic transmission predominantly in the superficial lamina, while postsynaptically enhancing NMDA receptor-mediated transmission in some neurons of the deep lamina. The antinociceptive effects of GBP may involve the inhibition of the release of excitatory amino acids from presynaptic terminals.     

Expression of 5-HT1A receptor mRNA in rat lumbar spinal dorsal horn neurons after peripheral inflammation

The present study observed the expression of the 5-hydroxytryptamine (5-HT) (1A) receptor mRNA in the lumbar spinal dorsal horn neurons following carrageenan inflammation using in situ hybridization (ISH). We also studied the co-localization of 5-HT(1A) receptor mRNA and gamma-amino butyric acid (GABA) or enkephalin (ENK) immunoreactivities using a combined fluorescent ISH and immunofluorescent histochemical double-staining technique. The finding of this study demonstrated that 5-HT(1A) receptor mRNA was widely distributed in the spinal dorsal horn with the highest density in laminae III-VI. Following carrageenan-induced inflammation, the 5-HT(1A) receptor mRNA expression in all layers of ipsilateral dorsal horn was significantly enhanced, and the peak occurred after 8h. Furthermore, the number of 5-HT(1A) receptor mRNA and GABA or ENK immunoreactive double-labeled cells was also markedly increased 8h after carrageenan injection. These findings suggested that following peripheral inflammation, the synthesis of 5-HT(1A) receptor was increased in the lumbar spinal dorsal horn neurons, especially in spinal GABA and ENK neurons.     

Reciprocal connections between the medullary dorsal reticular nucleus and the spinal dorsal horn in the rat

The synaptic architecture of spinal afferents of the dorsal portion (DRtd) of the medullary dorsal reticular nucleus (DRt) is studied. After iontophoretic injections of cholera toxin subunit B (CTb) into the superficial (laminae I-II), deep (laminae IV-V) or entire (laminae I-V) dorso-ventral extent of the spinal dorsal horn at the cervico-thoracic or lumbo-sacral levels, axonal boutons of two distinct types were labelled in the DRtd. Type A boutons (82% after cervico-thoracic injections and 92% after lumbo-sacral injections) were roundish, small and presented few mitochondria and small, round synaptic vesicles. Type B boutons (18% after cervico-thoracic injections and 8% after lumbo-sacral injections) were elongated, two to three times larger, and exhibited numerous mitochondria and larger round vesicles. Both types of bouton established asymmetrical synaptic contacts with small dendritic profiles and, less frequently, with dendritic trunks and perikarya. Retrograde labelling occurred in the postsynaptic profile of 15-18% type A boutons labelled from any injection site. Taken together with previous data on DRt-spinal synaptic contacts at the superficial dorsal horn, the present results point to the occurrence of a reciprocal excitatory loop connecting the dorsal DRt and lamina I, which may be at the basis of the DRt-mediated pain-facilitating effects described recently.     

Attempts to gauge the relative importance of pre- and postsynaptic effects of morphine on the transmission of noxious messages in the dorsal horn of the rat spinal cord

Both pre- and postsynaptic mechanisms have been proposed as an explanation of the depressive effects of opioids on the activity of nociceptive dorsal horn neurons. In order to gauge the importance of the two mechanisms, we studied the effect of morphine on the spontaneous hyperactivity of nociceptive dorsal horn neurons in the spinalized decerebrated deafferented rat (C5-Th1). In this preparation, intravenous morphine was shown to depress spontaneous firing rate in a dose-dependent fashion. A comparative analysis of the effect of the same dose of morphine (2 mg/kg i.v.) in the intact spinalized decerebrated arthritic rat, in which dorsal horn convergent neurons also display high spontaneous activity, revealed that systemic morphine is twice as potent when primary afferent fibers are left intact. These results can explain why the analgesic effect of morphine is more marked against pains due to an excess of nociception than against pains arising from deafferentation.     

Tonic descending inhibition affects intensity coding of nociceptive responses of spinal dorsal horn neurones in the cat

The supraspinal inhibitory control of lumbar spinal dorsal horn neurones was investigated in N2O-anaesthetized cats by reversibly blocking conduction in the spinal cord. Dorsal horn neurones selected for this study had convergent input from myelinated (A-) and unmyelinated (C-) fibres in the posterior tibial and/or superficial peroneal nerves of the hind limb. Virtually all of them could also be excited by noxious heating of the skin of the footpad region and by low intensity mechanical stimulation of the foot. Variation of the temperature of noxious radiant skin heating (40-56 degrees C, 10 sec in duration) resulted in graded responses of the neurones. The stimulus-response functions (SRF) were monotonic; in the majority of 32 cases they were linear. Neurones could be classified according to their maximum discharge frequency in response to skin heating into 22 weakly sensitive units (responses below 100 Hz at 50 degrees C) and 10 highly sensitive units (above 100 Hz). Responses outlasted the period of skin heating by seconds to minutes. A reversible conduction block of spinal axons by cooling a 15 mm cord segment (L1) with a thermode at 0 degrees C affected the responsiveness of the dorsal horn neurones in 12 of 15 cases. The maximum discharge frequency to a certain temperature of skin heating was increased during the spinal block. The duration of heat-evoked discharges was either not changed or increased during the spinal block. The SRF were reversibly displaced during the spinal blockade to higher discharge frequencies and lower threshold temperatures of skin heating. In 8 of 12 cases the change in the SRF was a nearly parallel shift, whereas in 4 units the increase of responsiveness had a complex effect upon the SRF. The decrease in the threshold to skin heating ranged up to 4.5 degrees C; the mean decrease was 2 degrees C. It is confirmed that in anaesthetized cats, nociceptive spinal neurones are subject to a tonically active descending inhibition, which is interrupted by local spinal cooling. The effect of the spinal block on the SRF of the neurones suggests that this tonic inhibition is similar to that produced by electrical stimulation in the lateral reticular formation of the brain-stem.