Coeruleospinal inhibition of nociceptive processing in the dorsal horn during unilateral hindpaw inflammation in the rat

Behavioral and neurochemical studies have shown that the coeruleospinal modulation system is activated by peripheral inflammation, and that this modulation system is active in only the dorsal horn ipsilateral, but not in the dorsal horn contralateral, to the site of inflammation; the present study was designed to confirm electrophysiologically this previous finding. Extracellular recordings from dorsal horn neurons were continued for at least 4 h after the induction of inflammation. Unilateral hindpaw inflammation was produced by a subcutaneous injection of carrageenan (2 mg in 0.15 ml saline). Background activity and responses to noxious heating were compared between rats receiving bilateral lesions in the locus coeruleus/subcoeruleus (LC/SC) and non-operated control rats. In neurons located in the dorsal horn ipsilateral to the inflamed paw, prior to inflammation, there was no significant difference in either the background activity or the heat-evoked response in neurons in LC/SC-lesioned compared to LC/SC-intact rats. Four hours after the induction of inflammation, there was a significant increase in both the background activity and heat-evoked response in neurons in LC/SC-lesioned compared to LC/SC-intact rats. In neurons located in the dorsal horn contralateral to the inflamed paw, 4 h after inflammation, no significant increase in either the background activity or the heat-evoked response in neurons in LC/SC-lesioned rats was observed, as well as in the case before inflammation. These results suggest that the coeruleospinal modulation system is active in only the dorsal horn ipsilateral, but not in the dorsal horn contralateral, to the site of inflammation during the development of unilateral hindpaw inflammation.     

Response properties of nociceptive and non-nociceptive neurons in the rat's trigeminal subnucleus caudalis (medullary dorsal horn) related to cutaneous and deep craniofacial afferent stimulation and modulation by diffuse noxious inhibitory controls

An electrophysiological study was carried out in anesthetized rats to characterize the properties of single neurons in trigeminal (V) subnucleus caudalis. Each neuron was functionally classified in terms of its cutaneous mechanoreceptive field properties as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR) or nociceptive-specific (NS), and its responsiveness was also tested to electrical stimulation of hypoglossal (XII) nerve muscle afferents. Some neurons were also tested with noxious stimulation of the tail or forepaw for the presence of diffuse noxious inhibitory controls (DNIC) of evoked responses. A mechanoreceptive field localized to the ipsilateral orofacial region was a feature of all the neurons which were located in laminae I-VI; the LTM neurons predominated in laminae III/IV whereas the nociceptive (WDR, NS) were located in the superficial and especially deeper laminae of caudalis. The majority of the WDR and NS neurons were also activated by noxious heating as well as by noxious mechanical and electrical stimulation of their orofacial mechanoreceptive field, and in contrast to our previous studies in cats, most of these caudalis nociceptive neurons received C fiber as well as A fiber cutaneous afferent inputs. In contrast to the LTM neurons, but consistent with our previous data in cats, many of the nociceptive neurons also received convergent excitatory inputs from XII muscle afferents, and the stimulus-response functions of the WDR neurons indicated that they were capable of coding the intensity of A and C fiber craniofacial muscle afferent inputs as well as those from cutaneous afferents. The study has also documented for the first time that muscle afferent-evoked responses as well as those evoked by cutaneous afferent inputs to nociceptive neurons are subject to DNIC. These findings indicate that subnucleus caudalis plays an important role in the transmission of superficial and deep nociceptive information from the craniofacial region of the rat, and also reveal that responses of the nociceptive neurons evoked by deep as well as superficial afferent inputs can be powerfully modulated by other nociceptive influences originating from widespread parts of the body.     

Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.

(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.     

Intracerebroventricular morphine decreases descending inhibitions acting on lumbar dorsal horn neuronal activities related to pain in the rat

Recordings were made from convergent neurons in the lumbar dorsal horn of the rat. These neurons were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hindpaw. Transcutaneous application of suprathreshold 2-msec square-wave pulses to the center of the receptive field resulted in responses to A- and C-fiber activation being observed: 27.2 +/- 2.2 (mean +/- S.E.M.) C-fiber latency spikes were evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic areas of the body; in particular, immersing the tail in a 52 degrees C waterbath caused a 74.2 +/- 2.0% inhibition of the C-fiber evoked responses; such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects of microinjections of morphine (0.6-40 micrograms; 2 microliter) within the 3rd ventricle on both the unconditioned C-fiber-evoked responses and the inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: 1) does i.c.v. morphine increase tonic descending inhibitory processes? and 2) what are the effects of i.c.v. morphine on descending inhibitory processes triggered phasically by noxious stimuli? The predominant effect of i.c.v. morphine on the C-fiber-evoked responses was a facilitation (17 of 26 cases). Such a facilitation was dose-related in the 0.6 to 40 microgram range and naloxone reversible; it plateaued from 20 min after the microinjection. No clear relationship was found between the number of C-fiber evoked responses in the control sequences and the subsequent effect of i.c.v. morphine. Intracerebroventricular morphine clearly reduced DNIC in the majority of cases (21 of 26). Such a reduction was dose-related in the 0.6 to 2.5 microgram range and naloxone reversible; it plateaued within 90 min of microinjection. No clear relationship was found between the changes in DNIC and either the number of C-fiber-evoked spikes in the control sequences or the changes in the C-fiber responses induced by i.c.v. morphine. Autoradiographic controls using [3H]morphine showed a labeling along the ventricle wall including the hypothalamus, the periaqueductal gray matter and the floor of the 4th ventricle, three regions which have been implicated in the control of nociceptive transmission at the spinal level. Diffusion from the ventricle wall was over a distance of 0.5 mm and was identical whether observed 20 or 95 min after the microinjections.(ABSTRACT TRUNCATED AT 400 WORDS)     

The organization of spinal pathways to ventrobasal thalamus in an experimental model of pain (the arthritic rat). An electrophysiological study

The spinal ascending pathways responsible for neuronal ventrobasal (VB) thalamic responses elicited by joint stimulation of the posterior paw were determined in arthritic rats used as a model of experimental pain. Responses of a same neurone to mechanical (movement--pressure--brushing) or thermal stimulation (50 degrees C) were analysed before and after discrete lesions in the white matter of the spinal cord. For 6 neurones responding exclusively to brushing applied on a small receptive field (RF) strictly contralateral to the recording site, responses were not altered as long as the contralateral dorsal column was intact. Twenty neurones exhibited bilateral symmetrical RF located on the posterior paws including the ankles and for some units the digits. They were driven by moderate pressure and/or mild sustained joint movement and by immersion in a hot water bath at 50 degrees C. Their responses were not significantly modified when the lesions destroyed most of the dorsal and the dorsolateral parts of the spinal cord. In 16/20 cases effect of one hemisection of the cord was studied: when the hemisection was contralateral to the recording site (n = 8) VB neuronal responses elicited from the paw ipsilateral to this side were eliminated in 6/8 cases; when the 1/2 section was ipsilateral to the recording site (n = 8) the lesion induced the elimination of the responses elicited from the paw opposite to the recorded VB for one unit only. The involvement of the spino-reticular pathways which have not only a crossed but also a non-crossed component is suggested. This hypothesis is discussed by comparison to data previously obtained, showing that by contrast in healthy rats the spino-thalamic tract is essential for VB neuronal responses to noxious stimuli.     

Indirect effects of intrathecal morphine upon diffuse noxious inhibitory controls (DNICs) in the rat

Diffuse noxious inhibitory controls (DNICs) affect all convergent neurones recorded in the dorsal horn of the spinal cord or the nucleus caudalis of the trigeminal system. They are triggered specifically by heterotopic noxious stimulation. DNICs acting at the trigeminal level were triggered by noxious thermal stimulation of caudal parts of the body, and the effects of intrathecal morphine applied at the coccygeal level were tested. The immersion of the right hind paw or of the tail induced inhibitions on C-fibre responses of trigeminal convergent neurones of 95.8 +/- 2.8% and 93.8 +/- 2.4+ respectively. Intrathecal morphine (15 micrograms; 20 microliters) produced an almost complete blockade of inhibitions triggered from the tail without significantly affecting those triggered from the hind paw. A reversal by systemic naloxone (0.4 mg/kg i.v.) was obtained in all cases. These results indicate that intrathecal morphine induced a segmental depression of nociceptive messages strong enough to prevent the spinal initiation of DNICs. We suggest that the segmental depression of nociceptive transmission induced by morphine led to a consequent blockade of DNICs acting on the whole population of convergent neurones not initially affected by the noxious stimulus. These findings are discussed with regard to the strong analgesic effects of intrathecal morphine observed in both behavioural and clinical studies.     

Noxious stimulation increases glutamate and arginine in the periaqueductal gray matter in rats: a microdialysis study

The periaqueductal gray matter (PAG) is an important center in the modulation of behavioral responses during nociception and stress. In the present experiment, extracellular excitatory amino acid overflow in the PAG was measured every 30 s during noxious stimulation. A combination of in vivo brain microdialysis in freely moving rats and capillary zone electrophoresis with laser induced-fluorescence detection allowed us to detect short lasting changes of excitatory amino acid in dialysates. A formalin injection in the hindpaw of the rat increased glutamate, arginine and aspartate concentration in PAG dialysates. This increase was calcium and nerve impulse-dependent, suggesting neuronal and glial origin of glutamate and arginine, respectively. Handling, pinching or saline injection in the hind paw did not increase glutamate showing that this neurochemical phenomenon is related to painful and persistent noxious stimulation. The results suggest that a rapid excitation of the PAG occurs during noxious stimulation. The role of glutamate and arginine in analgesia is discussed.     

Functional MRI detection of bilateral cortical reorganization in the rodent brain following peripheral nerve deafferentation

Evidence is emerging for significant inter-hemispheric cortical plasticity in humans, opening important questions about the significance and mechanism for this long range plasticity. In this work, peripheral nerve deafferentation was performed on both the rat forepaw and hindpaw and cortical reorganization was assessed using functional MRI (fMRI). Sensory stimulation of the forepaw or the hindpaw in rats that experienced only partial denervation resulted in activation in only the appropriate, contralateral, primary somatosensory cortex (SI). However, 2-3 weeks following complete denervation of the rats' forepaw or hindpaw, stimulation of the intact paw resulted in fMRI activation of ipsilateral as well as contralateral SI. To address whether inter-cortical communication is required for this cortical reorganization, the healthy hindpaw SI representation was stereotaxically lesioned in rats which had the other hindpaw denervated. No fMRI activation was detected in the ipsilateral SI cortex after lesioning of the contralateral cortex. These results indicate that extensive inter-hemispheric cortical-cortical reorganization can occur in the rodent brain after peripheral nerve deafferentation and that cortical-cortical connections play a role in mediating this inter-hemispheric cortical reorganization.     

Nerve injury-induced tactile allodynia is present in the absence of FOS labeling in retrogradely labeled post-synaptic dorsal column neurons

The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCY, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.     

The effects of a non-competitive NMDA receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation

The involvement of NMDA receptors in rats with peripheral inflammation and hyperalgesia was evaluated by administration of the non-competitive NMDA receptor antagonist, MK-801. Inflammation and hyperalgesia was induced by intradermal injection of complete Freund's adjuvant (CFA) or carrageenan into the left hind paw. The latency of paw withdrawal from a thermal stimulus was used as a measure of hyperalgesia in awake rats. MK-801 (1.6 mg/kg, i.p., or 31.5 μg, intrathecal) significantly attenuated thermal hyperalgesia and reduced its duration in comparison to saline-injected rats (P < 0.05). The receptive field size of nociceptive-specific and wide-dynamic-range neurons in the superficial and deep spinal dorsal horn recorded 24 h after injection of CFA was significantly reduced to 73 ± 6% (P < 0.05, n = 8) and 74 ± 4% (P < 0.05, n = 8) of control values, respectively, by a cumulative dose of 3 mg/kg of MK-801 (i.v.). MK-801 (2 mg/kg) prevented the expansion of the receptive fields of dorsal horn neurons recorded 5 ± 0.4 h (n = 5) after intradermal injection of CFA as compared to saline-injected rats (P < 0.05). MK-801 had no significant effect on receptive field size of dorsal horn neurons in rats without CFA-induced inflammation but blocked a transient expansion of the receptive fields induced by 1 Hz, C-fiber intensity electrical stimulation of the sciatic nerve. The background activity and noxious heat-evoked response of dorsal horn neurons in rats with CFA-induced inflammation were primarily inhibited and noxious pinch-evoked activity was both facilitated and inhibited by the administration of MK-801. These results support the hypothesis that NMDA receptors are involved in the dorsal horn neuronal plasticity and behavioral hyperalgesia that follows peripheral tissue inflammation.     

Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat

The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.     

Dorsal horn (convergent) neurones in the intact anaesthetized arthritic rat. II. Heterotopic inhibitory influences

Recordings were made from dorsal horn neurones in the spinal cord and trigeminal nucleus caudalis of intact anaesthetized rats. These rats had been rendered polyarthritic by s.c. injection of Mycobacterium butyricum suspended in oil into the base of the tail. The experiments were carried out during the acute phase of the illness (3-4 weeks post inoculation) during which hyperalgesia occurred. The disease mainly affected the hind paws and the tail and, to a lesser extent, the forepaws. The facial area of the animals was not at all affected. As described in a previous paper, recordings from lumbar dorsal horn neurones revealed that two subpopulations could be described on the basis of their electrophysiological characteristics. Namely, 'typical' units which include convergent, non-noxious and proprioceptive neurones and which have properties essentially similar to those found in healthy rats, and 'atypical' cells which have no counterpart in healthy rats and which include convergent and non-noxious neurones. All the typical convergent neurones were inhibited by noxious stimuli applied to heterotopic body areas, whereas typical non-noxious and proprioceptive neurones were not; these observations are similar to those described in healthy rats as diffuse noxious inhibitory controls (DNIC). However, it was also found that 88% of the atypical convergent and 85% of the atypical non-noxious cells were inhibited by various heterotopic stimuli. The most important observation was that gentle stimulation such as mild pressure applied to the inflamed contralateral ankle joint--a stimulus intensity which has never been found to be effective in healthy animals--was capable of triggering inhibition of both typical and atypical convergent neurones. Recordings from trigeminal nucleus caudalis neurones revealed that the entire population presented essentially the same properties as those observed in healthy animals in terms of activity evoked by natural or electrical stimulation of their excitatory receptive fields. The activity of non-noxious neurones was never modified by any heterotopically applied stimuli. By contrast, all convergent neurones were inhibited by heterotopic stimuli, noxious (52 degrees C, pinch) or non-noxious (light and mild pressure), applied to inflamed areas. While the inhibition triggered by noxious stimuli was reminiscent of that observed in healthy rats, the inhibition triggered by non-noxious mechanical stimuli was related to the inflammatory state of the part of the body stimulated, the most sensitive areas being the hind paws.(ABSTRACT TRUNCATED AT 400 WORDS)     

Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal Fos protein expression in rats with persistent inflammation.

This study examined the effect of electro-acupuncture (EA) on persistent inflammatory hyperalgesia in a rat model. Inflammation and hyperalgesia were induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of the rat. Hyperalgesia was determined by a decrease in paw withdrawal latencies (PWL) to a noxious thermal stimulus. EA was applied bilaterally at the acupuncture point Huantiao (G30) at the rat's hindlimbs. EA-treated rats (n = 11) had significantly longer PWLs as compared with placebo control rats (n = 7) in the inflamed paw at 2.5 hours and 5 days after injection of CFA (P <.05) and longer PWLs as compared to sham control rats (n = 9) at 2.5 hours (P >.05). Paw edema was significantly reduced in EA-treated rats versus placebo controls at 24 hours after inflammation (P <.01). Inflammation-induced spinal Fos expression in the medial half of laminae I-II in EA-treated rats versus placebo rats (n = 5 per group) was significantly reduced (P <.01). These data showed that EA delayed the onset and facilitated the recovery of inflammatory hyperalgesia and suppressed the inflammation-induced spinal Fos expression in neurons (laminae I-II) involved in receiving noxious stimulation. This rat model of persistent pain and inflammation seems to be an ideal animal model for studying the effect of acupuncture.     

Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia

The neuromodulatory interactions of sex steroids with the opioid system may result in sex differences in pain and analgesia. Dynorphin is an endogenous kappa-opioid peptide that is upregulated in an animal model of peripheral inflammation and hyperalgesia and is possibly regulated by circulating levels of sex steroids. The present study compared behavioral responses of male, cycling female, and gonadectomized Sprague-Dawley rats in a model of persistent pain. Cycling female rats were behaviorally tested over a 14-day period, and their estrous cycles were monitored by daily vaginal smears. Thermal hyperalgesia was measured by paw withdrawal latencies taken prior to and 24-72 h after rats received a unilateral hindpaw injection of complete Freund's adjuvant (CFA). Prior to CFA administration, there was no significant difference in paw withdrawal latencies between male rats, cycling female rats, and ovariectomized female rats. Following CFA administration, female rats in proestrus exhibited significantly increased hyperalgesia compared with male rats, ovariectomized female rats, and female rats in other estrous stages (P相似文献   

Gastrocardiac afferent convergence in upper thoracic spinal neurons: a central mechanism of postprandial angina pectoris.

The aim of this study was to examine whether gastric afferent information converged onto upper thoracic spinal neurons that received noxious cardiac input. Extracellular potentials of single upper thoracic (T3) spinal neurons were recorded in pentobarbital-anesthetized, paralyzed, ventilated male rats. Gastric distension (GD) (20, 40, 60 mm Hg, 20 seconds) was produced by air inflation of a latex balloon surgically placed in the stomach. A catheter was placed in the pericardial sac to administer bradykinin solution (10 microg/mL, 0.2 mL, 1 minute) as a noxious cardiac stimulus. Noxious GD (> or =40 mm Hg) altered activity of 26 of 31 (84%) spinal neurons receiving cardiac input. Twenty-two (85%) gastrocardiac convergent neurons were excited, and 1 neuron was inhibited by both intrapericardial bradykinin and GD; the remainder exhibited biphasic response patterns. Twenty-three of 26 (88%) gastrocardiac neurons also received convergent somatic input from the chest, triceps, and upper back areas. Bilateral cervical vagotomy did not significantly affect excitatory responses to GD in 5 of 5 neurons tested. Spinal transection at the C1 segment after vagotomy did not affect excitatory responses to GD in 3 of 4 neurons but abolished the GD response in 1 neuron. These data showed that a gastric stimulus excited T3 spinal neurons with noxious cardiac input primarily by way of intraspinal ascending pathways. PERSPECTIVE: Convergence of gastric afferent input onto upper thoracic spinal neurons receiving noxious cardiac input that was observed in the present study may provide a spinal mechanism that explains stomach-heart cross-organ communication, such as postprandial triggering and worsening of angina pectoris in patients with coronary artery disease.     

Relationship between electroacupuncture analgesia and descending pain inhibitory mechanism of nucleus raphe magnus

Raphe-spinal (R-S) neurons were identified in the nucleus raphe magnus (NRM). The conduction velocity of their axons was calculated to be about 15-60 m/sec. The great majority of R-S neurons did not respond clearly to non-noxious stimuli, such as brushing hair or lightly pressing the skin, but they did respond to noxious stimuli (pricking or clamping), with increases or decreases in their firing rates. The receptive fields of the R-S neurons responding to noxious stimuli were very wide covering almost all of the body. The responses of R-S neurons to noxious stimulation were excitatory (increasing firing rates), inhibitory (decreasing) and unresponsive in type, and we unexpectedly found 3 reversibly excitatory-inhibitory type R-S neurons, the firing rate of inhibitory R-S neurons being higher than that of excitatory R-S neurons. The responses of the excitatory-inhibitory reversible neurons to noxious stimulation were also related to the background firing rates. The effects of electroacupuncture (EA) on the excitatory R-S neurons were mainly to increase their firing rates, and to inhibit their nociceptive responses. After the transection of DLF, the R-S neurons could still be activated by EA, but the post-inhibitory effects of EA on their nociceptive responses were obviously reduced. It is suggested that the EA can activate NRM, a supraspinal area mediating a negative feedback circuit modulating pain, thus inducing analgesia via descending inhibition.     

Neuromodulation of thoracic intraspinal visceroreceptive transmission by electrical stimulation of spinal dorsal column and somatic afferents in rats.

Clinical studies have shown that neuromodulation therapies, such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS), reduce symptoms of chronic neuropathic and visceral pain. The neural mechanisms underlying SCS and TENS therapy are poorly understood. The present study was designed to compare the effects of SCS and TENS on spinal neuronal responses to noxious stimuli applied to the heart and esophagus. Direct stimulation of an intercostal nerve (ICNS) was used to simulate the effects of TENS. Extracellular potentials of left thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated male rats. SCS (50 Hz, 0.2 ms, 3-5 minutes) at a clinical relevant intensity (90% of motor threshold) was applied on the C1-C2 or C8-T1 ipsilateral spinal segments. Intercostal nerve stimulation (ICNS) at T3 spinal level was performed using the same parameters as SCS. Intrapericardial injection of bradykinin (IB, 10 microg/mL, 0.2 mL, 1 minute) was used as the noxious cardiac stimulus. Noxious thoracic esophageal distension (ED, 0.4 mL, 20 seconds) was produced by water inflation of a latex balloon. C1-C2 SCS suppressed excitatory responses of 16/22 T3 spinal neurons to IB and 25/30 neurons to ED. C8-T1 SCS suppressed excitatory responses of 10/15 spinal neurons to IB and 17/23 neurons to ED. ICNS suppressed excitatory responses of 9/12 spinal neurons to IB and 17/22 neurons to ED. These data showed that SCS and ICNS modulated excitatory responses of T3 spinal neurons to noxious stimulation of the heart and esophagus. PERSPECTIVE: Neuromodulation of noxious cardiac and esophageal inputs onto thoracic spinal neurons by spinal cord and intercostal nerves stimulation observed in the present study may help account for therapeutic effects on thoracic visceral pain by activating the spinal dorsal column or somatic afferents.     

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.     

Do convergent neurones in the spinal dorsal horn discriminate nociceptive from non-nociceptive information?

Thirty convergent neurones responding to both noxious and non-noxious cutaneous stimuli were recorded at the lumbar level in either anaesthetized 'intact' rats or unanaesthetized 'spinal' rats. Their responses to radiant heat application and to repetitive innocuous mechanical stimulation of the centre of their receptive fields were analysed, both in terms of the maximal and the mean firing rates. These neurones increased their discharge rates in relation to the temperature applied to their receptive fields with the highest levels being produced by noxious intensities. This finding confirms earlier reports suggesting the capacity of these neurones to encode nociceptive information of thermal origin. However, a very high level of firing could also be evoked by repetitively applied innocuous mechanical stimuli. This was a consistent finding, observed both in intact and spinal animals, which was true for the two subgroups into which we divided the convergent neurones (warming/noxious heat units and noxious heat units). These results are discussed in terms of the role of convergent neurones in nociception. It is suggested that a single channelled signal emanating from these neurones could not be the basis of a clear nociceptive message to the brain; two alternative hypotheses involving multichannelled organizations of impulses are proposed for discussion.     

Convergence of cutaneous and pelvic visceral nociceptive inputs onto primate spinothalamic neurons

The responses of 66 primate spinothalamic neurons to natural stimulation of the urinary bladder and testicle were studied with extracellular recording techniques in order to elucidate the neural basis for referral of visceral pain. Thirty-eight out of 53 cells located at the thoraco-lumbar junction or in sacral segments responded to noxious cutaneous stimuli, and 84% of these also exhibited phasic and/or tonic excitatory responses to distension of the urinary bladder. Seventeen out of 20 of these units, all located at the thoraco-lumbar junction, were excited by compression of the ipsilateral testicle. The response was graded with the compressive force. Excitatory responses to noxious heat and an irritant chemical (KCl) applied to the exposed testicular surface were also observed. Twelve sacral units having inputs from deep receptors of the tail exhibited mixed excitatory and inhibitory responses to bladder distension. A further 2 cells located at the thoracolumbar junction responded only to cutaneous tactile stimuli, and 13 cells located at the lumbosacral enlargement were tonically inhibited by bladder distension.It is concluded that spinothalamic neurons that convey nociceptive input from the skin may also respond to noxious visceral stimuli. Such viscerosomatic convergence provides a neural substrate for the phenomenon of cutaneous referral of visceral pain.