Antinociceptive effect of morphine on rat spinothalamic tract and other dorsal horn neurons

The importance of the spinothalamic tract in pain transmission makes it an attractive candidate for study with respect to the effects of antinociceptive compounds. We have been interested in the analgesic actions of opioids and noradrenergic agents at the spinal level and have investigated the effects of these agents on extracellularly recorded nociceptive dorsal horn neurons in the rat. Spinothalamic tract cells were identified by antidromic activation from the somatosensory thalamus. Morphine was administered by bathing the spinal cord in an artificial cerebrospinal fluid solution which contained a known concentration of drug. We observed a dose-related inhibition, naloxone-reversible in some cases, of activity produced by spinally administered morphine in identified rat spinothalamic tract cells and dorsal horn nociceptive neurons. Morphine had no effect on stimulus-evoked responses of low threshold dorsal horn neurons.     

Organization of the serotonergic innervation of spinal neurons in rats—I. Neuropeptide coexistence in varicosities innervating some spinothalamic tract neurons but not in those innervating postsynaptic dorsal column neurons

Previous studies have suggested that peptides such as substance P and thyrotropin-releasing hormone coexist with serotonin in the same varicosities in the ventral horn and intermediate gray of the spinal cord in rat. However, coexistence of these peptides with serotonin is rare in fibers in the superficial dorsal horn. Since it has been proposed that serotonergic fibers in the superficial dorsal horn act to modulate nociception, it was hypothesized that the serotonergic neurons that contain neither substance P nor thyrotropin-releasing hormone might constitute a specifically antinociceptive subset of serotonergic neurons. This being the case, it would be expected that different types of serotonergic neurons innervate nociceptive and non-nociceptive spinal neurons. In order to test this hypothesis, a group of cells that include nociceptive neurons (spinothalamic tract neurons) and a group of predominantly non-nociceptive neurons (postsynaptic dorsal column neurons) in the spinal cord of rat were retrogradely labeled. Sections of the spinal cord containing retrogradely labeled spinothalamic tract or postsynaptic dorsal column neurons were stained for serotonin and either substance P or thyrotropin-releasing hormone using two-color immunohistochemistry. A retrogradely labeled cell was classified as “apposed” if there was no discernible distance between an immunohistochemically labeled varicosity and the cell. Eighty per cent of spinothalamic tract and 83% of postsynaptic dorsal column profiles were apposed by serotonin-immunoreactive varicosities in the spinal cord. Thirty-one per cent of the spinothalamic tract profiles that were apposed by serotonergic varicosities were apposed by serotonergic varicosities that were also stained for thyrotropin-releasing hormone. The distribution of the latter spinothalamic neurons was similar to that reported for spinothalamic tract neurons responsive to joint movement. In addition, at least 63% of the spinothalamic tract profiles which were apposed by serotonergic varicosities were apposed by “serotonin-only” varicosities, including most spinothalamic tract neurons in the marginal zone, suggesting that at least some “serotonin-only” neurons are antinociceptive. However, contrary to the hypothesis, at least 94% of the postsynaptic dorsal column profiles apposed by serotonergic varicosities were apposed by “serotonin-only” varicosities.

These findings suggest that there may be a relationship between the sensory modality to which a spinal neuron responds and the type of serotonergic innervation it receives. However, it appears that “serotonin-only” neurons may not constitute a specifically antinociceptive category of serotonergic neurons.     

Ventrolateral and dorsolateral ascending spinal cord pathway influence on thalamic nociception in cat

1. In cat there are two portions of the spinothalamic tract (STT)--a ventral component, the ventral spinothalamic tract (VSTT) made up of axons of cells of spinal cord laminae IV-X, and a dorsolateral component, the dorsolateral spinothalamic tract (DSTT) made up of axons of cells in lamina I of the spinal cord dorsal horn. This study was designed to evaluate thalamic neuronal responses to cutaneous noxious thermal stimuli and to determine the functional importance of pathways ascending in the ventral and dorsolateral portions of the spinal cord, ipsilateral to the thalamic recording site and contralateral to the hindlimb stimulation region, for transmission of nociceptive information to the thalamus. 2. Extracellular single-unit recordings were made from 45 neurons in the ventrobasal complex (VBX) of cat thalamus. Thirty-five of these units responded either exclusively or preferentially to noxious cutaneous stimuli. Responses to noxious thermal stimuli applied to the unit's receptive fields were obtained, and then the effects on these responses of blocking conduction through the dorsolateral funiculus (DLF) and the ventrolateral quadrant (VQ) of the thoracic spinal cord ipsilateral to the thalamic recording site were determined. DLF and VQ conduction blocks were accomplished with the use of a cold probe technique and, at times, surgical lesions of the appropriate portion of the spinal cord. 3. The nociceptive units were located in the periphery of the ventral posterior lateral nucleus (VPL) of the thalamus. Their locations corresponded to the somatotopic organization of VPL. Nociceptive thermal responses were found in both high-threshold (HT) (10 cells) and wide-dynamic-range (WDR) (22 cells) units. The receptive fields of these units were generally small and were located on the hindlimb contralateral to the recording site. The thermoreceptive units had thresholds between 44 and 48 degrees C and were able to code for stimulus intensity. 4. Nine of the 35 nociceptive units demonstrated a decrease in response and two units an increase in response to noxious cutaneous stimulation during DLF block ipsilateral to the recording site and contralateral to the cutaneous stimulation site, whereas four units demonstrated a decrease in response and one unit an increase in response to noxious thermal cutaneous stimulation during VQ block ipsilateral to the recording site and contralateral to the cutaneous stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influences of central gray matter stimulation on thalamic neuron responses to high- and low-threshold stimulation of trigeminal nerve structures

Responses of the thalamic non-specific medial nuclei and relay ventral posteromedial nucleus neurons evoked by stimulation of the teeth pulp of A alpha and A sigma fibers of infraorbital nerve and caudal nucleus of the spinal trigeminal tract were studied in cats under thiopental-chloralose anesthesia. Three groups of neurons were revealed: low-threshold, high-threshold and convergent. In medial nuclei, 29% of neurons formed the low-threshold group, 12% made up the high-threshold group and 59% were convergent. In the ventral posteromedial nucleus 47% of neurons formed the low-threshold group, 4% made up the high-threshold group and 49% were convergent. Ninety per cent of the medial nuclei neurons and 79% of the ventral posteromedial nucleus neurons responded to stimulation of the caudal nucleus spinal trigeminal tract. The conditioning central gray matter stimulation could suppress responses of low-threshold, high-threshold and convergent neuron groups. In medial nuclei 100% of responses induced by stimulation of teeth pulp and A sigma fibers of the infraorbital nerve were completely suppressed and 86% of responses induced by stimulation of the A alpha fibers of the infraorbital nerve stimulation were also completely suppressed. In the ventral posteromedial nucleus 40% of responses induced by stimulation of teeth pulp and A sigma fibers of the infraorbital nerve were completely suppressed and 26.4% of responses induced by stimulation of the A alpha fibers of the infraorbital nerve were completely suppressed. Conditioning stimulation of the central gray matter suppressed responses evoked by stimulation of the caudal nucleus spinal trigeminal tract and in the most part neurons of the medial nuclei and neuron responses of the ventral posteromedial nucleus. The inhibitory influence of central gray matter stimulation on neuronal responses evoked by stimulation of the caudal nucleus spinal trigeminal tract shows that the central gray matter had a direct influence on the activity of thalamic neurons.     

The effects of intrathecally applied noradrenaline and 5-hydroxytryptamine on spinal nocifensive reflexes and the rostral transmission of noxious information to the thalamus in the rat

The effects of intrathecally applied noradrenaline (NA) and 5-hydroxytryptamine (5-HT) on a spinal nocifensive reflex and nociceptive responses recorded from rat ventrobasal thalamus have been compared. A dose of 15 nmol NA increased the tail flick latency (TFL) for approximately 120 min (n = 12) in rats lightly anaesthetised with Saffan. A dose of 260 nmol 5-HT increased the TFL for approximately 21 min (n = 7). In rats anaesthetised with urethane, 15 nmol NA produced a reversible reduction in the response of 15 ventrobasal thalamic units to noxious stimulation lasting approximately 36 min (n = 15). A dose of 260 nmol 5-HT reduced thalamic nociceptive responses for approximately 25 min (n = 12). This suggests that spinal interneurones subserving the tail flick reflex are more sensitive to NA than spinal neurones involved in the transmission of noxious information supraspinally. In contrast, intrathecally applied 5-HT is equipotent in its action on both groups of neurones involved in nociceptive mechanisms.     

Strychnine alters response properties of trigeminal nociceptive neurons in the rat.

The purpose of this study was to examine the role of glycine in sensory processes in the spinal trigeminal nucleus oralis (Sp5O). We evaluated the effect of intravenous administration of strychnine, a glycine receptor antagonist, on the responses of Sp5O convergent neurons evoked by innocuous peripheral electrical and mechanical stimuli in halothane-anesthetized rats. Strychnine significantly increased the Abeta-fiber-evoked activities of Sp5O neurons to electrical stimulation in a dose-dependent (0.2-0.8 mg/kg) fashion. The response to air-jet stimulation was also significantly enhanced at the highest dose of strychnine. These findings indicate that glycinergic neurons participate in the control of the flow of information conveyed to Sp5O nociceptive neurons by myelinated low-threshold mechanoreceptive afferents. Thus, alteration of trigeminal glycinergic modulation may contribute to the dynamic mechanical allodynia that occurs in trigeminal neuropathies.     

Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat

The effects of cannabinoid agonists on noxious heat-evoked firing of 62 spinal wide dynamic range (WDR) neurons were examined in urethan-anesthetized rats (1 cell/animal). Noxious thermal stimulation was applied with a Peltier device to the receptive fields in the ipsilateral hindpaw of isolated WDR neurons. To assess the site of action, cannabinoids were administered systemically in intact and spinally transected rats and intraventricularly. Both the aminoalkylindole cannabinoid WIN55,212-2 (125 microg/kg iv) and the bicyclic cannabinoid CP55,940 (125 microg/kg iv) suppressed noxious heat-evoked activity. Responses evoked by mild pressure in nonnociceptive neurons were not altered by CP55,940 (125 microg/kg iv), consistent with previous observations with another cannabinoid agonist, WIN55,212-2. The cannabinoid induced-suppression of noxious heat-evoked activity was blocked by pretreatment with SR141716A (1 mg/kg iv), a competitive antagonist for central cannabinoid CB1 receptors. By contrast, intravenous administration of either vehicle or the receptor-inactive enantiomer WIN55,212-3 (125 microg/kg) failed to alter noxious heat-evoked activity. The suppression of noxious heat-evoked activity induced by WIN55,212-2 in the lumbar dorsal horn of intact animals was markedly attenuated in spinal rats. Moreover, intraventricular administration of WIN55,212-2 suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, both vehicle and enantiomer were inactive. These findings suggest that cannabinoids selectively modulate the activity of nociceptive neurons in the spinal dorsal horn by actions at CB1 receptors. This modulation represents a suppression of pain neurotransmission because the inhibitory effects are selective for pain-sensitive neurons and are observed with different modalities of noxious stimulation. The data also provide converging lines of evidence for a role for descending antinociceptive mechanisms in cannabinoid modulation of spinal nociceptive processing.     

Intrathecally administered apomorphine or LY171555 reduces nociceptive responses recorded from ventrobasal thalamic neurones in urethane anaesthetised rats

The effects of intrathecal injections of the D2 agonists apomorphine and LY171555 were studied on responses of ventrobasal neurones responding to noxious stimulation in the urethane anaesthetised rat. At a dose of 75 micrograms/kg the D2 agonists had little effect on a total of 18 thalamic neurones. A higher dose (100 micrograms/kg) produced a reversible reduction of thalamic nociceptive responses on 15 occasions. A transient fall in blood pressure usually accompanied the intrathecal injection of the agonists. These results suggest that dopamine can modulate the transmission of nociceptive information to the thalamus and also suggests a role in the processing of autonomic function.     

The cannabinoid receptor agonist, WIN 55,212-2, inhibits cool-specific lamina I medullary dorsal horn neurons

Cannabinoid receptor agonists have been demonstrated to inhibit medullary and spinal cord dorsal horn nociceptive neurons. The effect of cannabinoids on thermoreceptive specific neurons in the spinal or medullary dorsal horn remains unknown. In the present study, single-unit recordings from the rat medullary dorsal horn were performed to examine the effect of a cannabinoid receptor agonists on cold-specific lamina I spinothalamic tract neurons. The cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (WIN-2), was locally applied to the medullary dorsal horn and the neuronal activity evoked by cooling the receptive field was recorded. WIN-2 (1 microg/microl and 2 microg/microl) significantly attenuated cold-evoked activity. Co-administration of the CB1 receptor antagonist SR 141716 with WIN-2 did not affect cold-evoked activity. These results demonstrate a potential mechanism by which cannabinoids produce hypothermia, and also suggest that cannabinoids may affect non-noxious thermal discrimination.     

The spinothalamic tract in the primate: a re-examination using wheatgerm agglutinin conjugated to horseradish peroxidase

The sites of termination of the primate spinothalamic tract have been reinvestigated using the anterograde transport of wheatgerm agglutinin conjugated to horseradish peroxidase. Monkeys which received an injection of the conjugate at the spinal cervical level (C7-C8) displayed a "patchy" pattern of labelling in the coronal plane in the ventral posterior lateral and caudal ventrolateral nucleus. In three dimensional reconstructions this labelling appeared to be rod-like in shape. A more homogeneous pattern of labelling was present in parts of the central lateral, posterior, suprageniculate, limitans, submedius, medial dorsal, paracentral, central medial, reuniens and periventricular nucleus. Lumbar injections (L2-L3) produced a similar although less intense pattern of labelling with only the ventral posterior lateral and ventrolateral nuclei displaying an obvious topological organization. Comparison of these results with previous physiological and pharmacological reports suggests several morphological-functional correlations: first, that both the discriminative and motivational/arousal aspects of spinothalamic tract function, associated with the lateral and medial thalamic nuclei, respectively, may be conveyed by direct spinothalamic tract projections. In support of this hypothesis medial spinothalamic tract termination sites receive a homogeneous input which does not have an obvious topographical organization, whereas lateral spinothalamic tract termination sites receive a "patchy" pattern of terminals which are topographically organized; second, that the patchy pattern of labelling observed in the coronal plane in the lateral thalamus corresponds to a "rodlike" pattern of labelling in three dimensions. This "rodlike" pattern of labelling has previously been observed for medial lemniscal projections to the thalamus and has been postulated to be the thalamic equivalent of cortical "columns"; third, that there appears to be a tight overlap between spinothalamic tract terminals and opiate receptor binding in some medial but not lateral thalamic nuclei. Such an overlap may be indicative of a pharmacological difference in the types of spinothalamic tract inputs which could be modulated by opiates at the thalamic level.     

Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus

A major ascending nociceptive pathway from spinal lamina I to the mesencephalon has previously been reported in the cat, rat and monkey. In the present paper, we have used single and double retrograde labeling techniques to describe this projection system and its collateralization to the thalamus in the rat. Injections of wheat germ agglutinin-horseradish peroxidase into the pontomesencephalic parabrachial area labeled cell bodies bilaterally in lamina I and deeper laminae of the spinal cord. Bilateral lesions of the dorsolateral funiculi at thoracic levels reduced labeling of lamina I neurons caudal to the lesions. Combined injections of fluorescent retrograde tracers into the lateral thalamus and parabrachial area resulted in double labeling of projection neurons in lamina I, lamina IV VIII and the lateral spinal nucleus of the cervical and lumbar enlargements. Double-labeled neurons were especially abundant in lamina I. Thus, we have demonstrated a major lamina I projection through the dorsolateral funiculi to the parabrachial area with significant collateralization to the thalamus. Moreover, since more than 80% of retrogradely labeled lamina I spinothalamic tract cells had collaterals to the parabrachial area we have indirectly demonstrated the presence of a dorsolateral funicular pathway for lamina I spinothalamic neurons in the rat. More lamina I neurons were retrogradely labeled from midbrain injections as compared to thalamic injections. The significance of these findings rest on previous work in this and other laboratories and concerns the understanding of spinal nociceptive mechanisms. Lamina I projection neurons are primarily nociceptive-specific in their response properties and have been shown to project to both the midbrain and thalamus via the dorsolateral funiculus in a number of species. The role of this projection system in nociceptive transmission may lie in its ability to distribute precise information to multiple brain stem sites which in turn activate autonomic or affective responses or descending pain modulatory mechanisms.     

Convergence of nociceptive and non-nociceptive inputs onto spinal reflex pathways to the tibialis anterior muscle in humans

The interaction of low-threshold mechanoreceptive and nociceptive inputs onto spinal neurones probably plays a major role in the pathophysiology of the clinical sign of allodynia. This phenomenon was investigated by modulation of the early component of the flexor reflex (FR) in the tibialis anterior (TA) muscle, elicited by electrical stimulation of the medial plantar nerve at the sole of the foot, by homotopically applied painful heat in humans. This early reflex with an electrical threshold of 2.7-fold the detection threshold and a mean afferent conduction velocity of 49 m s^?1 is a non-nociceptive FR. When applying conditioning painful heat (46 °C) to the sole of the foot this reflex was significantly increased by a factor of 3.4 (non-painful electrical stimuli; n = 5) and 2.0 (painful electrical stimuli; n = 11). The onset latencies were significantly shortened from 74.2 to 64.0 ms and 69.6 to 63.7 ms, respectively. A late nociceptive FR was also facilitated. While the Hoffmann reflex (HR) in the TA muscle was nearly abolished by painful heat, the HR in the soleus (SO) muscle remained unchanged. These data suggest a convergence of low-threshold mechanoreceptive and nociceptive inputs onto spinal reflex pathways in humans, probably at an interneuronal level in humans.     

The effects of SDZ NKT 343, a potent NK1 receptor antagonist, on cutaneous responses of primate spinothalamic tract neurones sensitized by intradermal capsaicin injection

Substance P, acting through neurokinin I receptors, is involved in the processing of nociceptive information in the spinal cord. Sensitization of spinothalamic tract neurons occurs to low-intensity stimuli following capsaicin injection. The current study tested the effects of the novel neurokinin 1 receptor antagonist, SDZ NKT 343, on the sensitization of spinothalamic tract cells by capsaicin in monkeys. Spinothalamic tract cells from the lumbar enlargement with receptive fields in the hindpaw were isolated and recorded before and after intradermal injection of capsaicin. The background activity and responses to brushing, pressing and pinching the skin were assessed. Thirty minutes after capsaicin injection there was an increase in background activity and responses to brush and pressure applied to the receptive field. Infusion of SDZ NKT 343 (for 30–45 min) significantly reversed the increased response to brushing without affecting the increased background activity or the increased response to pressure. Thus, blockade of neurokinin 1 receptors reduces the sensitized responses to innocuous mechanical stimuli but not to noxious mechanical stimuli. Received: 2 March 1998 / Accepted: 24 April 1998     

Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp

We have recently demonstrated that application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces central sensitization that is reflected in changes in spontaneous activity, mechanoreceptive field (RF) size, mechanical activation threshold, and responses to graded mechanical stimuli applied to the neuronal RF in trigeminal brainstem subnucleus caudalis and subnucleus oralis. The aim of this study was to test whether central sensitization can be induced in nociceptive neurons of the posterior thalamus by MO application to the pulp. Single unit neuronal activity was recorded in the ventroposterior medial nucleus (VPM) or posterior nuclear group (PO) of the thalamus in anesthetized rats, and nociceptive neurons were classified as wide dynamic range (WDR) or nociceptive-specific (NS). MO application to the pulp was studied in 47 thalamic nociceptive neurons and found to excite over 50% of the 35 VPM neurons tested and to produce significant long-lasting (over 40 min) increases in spontaneous activity, cutaneous pinch RF size and responses to graded mechanical stimuli, and a decrease in threshold in the 29 NS neurons tested; a smaller but statistically significant increase in mean spontaneous firing rate and decrease in activation threshold occurred following MO in the six WDR neurons tested. Vehicle application to the pulp did not produce any significant changes in six VPM NS neurons tested. MO application to the pulp produced pronounced increases in spontaneous activity, pinch RF size, and responses to mechanical stimuli, and a decrease in threshold in three of the six PO neurons. In conclusion, application of the inflammatory irritant MO to the tooth pulp results in central sensitization of thalamic nociceptive neurons and this neuronal hyperexcitability likely contributes to the behavioral consequences of peripheral inflammation manifesting as pain referral, hyperalgesia and allodynia.     

Spinal effects of the calmodulin inhibitor calmidazolium on dorsal horn neurons in the rat

Drugs able to inhibit calmodulin activation can prevent some consequences of the rise in intracellular calcium. It has recently been shown that intrathecal injection of calmodulin inhibitors induce analgesia in rats. We study here the effect induced by the calmodulin inhibitor, calmidazolium, on the activity of dorsal horn neurons driven by noxious and non-noxious stimuli. Extracellular recordings of convergent (n = 12), low-threshold mechanoreceptive (n = 5) and proprioceptive (n = 5) units were made in the presence of calmidazolium. Calmidazolium (600 micrograms) reduced the noxious (50 degrees C) heat-evoked responses obtained in convergent neurons. On the contrary, the non-noxious tactile responses obtained in low-threshold mechanoreceptive neurons as well as the joint movement-evoked responses obtained in proprioceptive units remained unmodified. We conclude that calmidazolium can block nociceptive processing in the spinal cord and that this fact can help to explain the analgesic effects that intrathecal W-7 and calmidazolium induce in behavioral tests.     

Functional plasticity in primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord

The long-term consequences of thoracic spinothalamic tract lesion on the physiological properties of neurons in the ventral posterior lateral nucleus of the thalamus in monkeys were assessed. Neurons responding to both compressive and phasic brush stimuli (multireceptive neurons), but not brush-specific (low-threshold) neurons, in the partially deafferented thalamus showed increased spontaneous activity, increased responses evoked by cutaneous stimuli and larger mean receptive field size than the same types of cells in the thalamus with intact innervation. The spike train properties of both the spontaneous and evoked discharges of cells were also altered so that there was an increased incidence of spike-bursts in cells of deafferented thalamus. These changes were widespread in the thalamus, and included cells in both the fully innervated forelimb representation and the partially denervated hindlimb representation ipsilateral to the lesion. The spontaneous and evoked spike trains in the ipsilateral thalamus also show increased frequency of both spike-burst and non-burst events compared to the intact thalamus. These results indicate that chronic spinothalamic tract lesion produces widespread changes in the physiological properties of a discrete cell population of the thalamus.The findings in this study indicate that the thalamic processing of somatosensory information conveyed by the lemniscal system is altered by transection of the spinothalamic tract. This change in sensory processing in the thalamus would result in altered cortical processing of innocuous somatosensory inputs following deafferentation and so possibly contribute to the generation of the central pain syndrome.     

Responses of primate spinothalamic tract neurons to electrical stimulation of hindlimb peripheral nerves.

The responses of spinothalamic tract neurons were studied by extra- and intracellular recordings from the lumbosacral spinal cord in anesthetized rhesus monkeys (Macaca mulatta). The neurons were identified by antidromic activation from the contralateral diencephalon. They were then classified by the mildest form of mechanical stimulation applied to the ipsilateral hindlimb. The effects of electrical stimulation of the nerve(s) supplying the receptive field were investigated. Graded electrical stimulation revealed that the threshold responses of spinothalamic tract neurons excited by weak mechanical stimuli occurred when the largest afferent fibers were activated. On the other hand, neurons that required intense mechanical stimulation for their excitation tended to have higher thresholds to electrical stimulation. Some spinothalamic tract cells were shown to receive monosynaptic excitatory connections from peripheral nerve fibers, although polysynaptic connections may generally be more important. An input from unmyelinated afferent fibers was demonstrated. It is concluded the primate spinothalamic tract neurons receive a rich convergent input from a variety of cutaneous receptors. The experiments provide some evidence for the most likely types of receptors.     

The effects of microinjection of morphine into thalamic nucleus submedius on formalin-evoked nociceptive responses of neurons in the rat spinal dorsal horn

Previous studies have indicated that the thalamic nucleus submedius (Sm), as an ascending component, is involved in an endogenous analgesic system consisting of spinal cord-Sm-ventrolateral orbital cortex (VLO)-periaqueductal gray (PAG)-spinal cord loop. To investigate the action of opioid in this antinociception pathway, the effects of microinjection of morphine and naloxone into the Sm on the formalin-induced nociceptive responses of neurons in the spinal dorsal horn were determined in the anesthetized rat. Formalin (5%, 50 microl) subcutaneously injected into unilateral hindpaw produced a biphasic nociceptive response which was similar to that obtained from assessing the nociceptive behavior either in the relative magnitude of response or the time course. A unilateral microinjection of morphine (5 microg, 0.5 microl) into the Sm 15 min after formalin injection significantly depressed the second phasic responses of neurons induced by formalin, and this effect was significantly attenuated by pre-microinjection of opioid receptor antagonist naloxone (1 microg, 0.5 microl) into the same site. The results suggest that the Sm is involved in opioid receptor-mediated antinociceptive effect on the persistent nociception through depression of the nociceptive transmission at the spinal cord level.     

Depression by nicotine of pain-related nociceptive activity in the rat thalamus and spinal cord

Summary To assess the possible role of nicotinergic control in nociception and pain, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was elicited by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurones in the thalamus and from ascending axons in the spinal cord. Intravenous administration of nicotine (0.01–0.5 mg/kg) depressed the nociceptive activity evoked in the thalamus and the spinal cord in a dose-dependent way. The maximum depression in thalamus and spinal cord was 40% of control activity and obtained at a dose of 0.025 mg/kg. Likewise, local administration of nicotine to the spinal cord by intrathecal injection (5, 10, and 30 g) reduced the nociceptive activity evoked in neurones of the thalamus and in ascending axons of the spinal cord, the maximum of the depression being 40% of control activity. The depressant effect of nicotine (0.05 mg/kg) was reduced by mecamylamine (1 mg/kg) but not by atropine (0.5 mg/kg). It is concluded that the antinociceptive effect of nicotine is due to a specific action of the alcaloid at the spinal level.     

Functional organization of trigeminal subnucleus interpolaris: nociceptive and innocuous afferent inputs, projections to thalamus, cerebellum, and spinal cord, and descending modulation from periaqueductal gray

In view of continuing uncertainties concerning the organization, afferent inputs, and projection sites of neurons in the subnucleus interpolaris of the trigeminal (V) spinal tract nucleus, the characteristics of 222 single neurons in and adjacent to the subnucleus were examined electrophysiologically in adult cats anesthetized with chloralose. Neurons were tested for orthodromic responsiveness to a variety of stimuli that included nonnoxious tactile stimuli, noxious mechanical and radiant-heat stimuli, and graded electrical stimulation of the skin, mucosa, tooth pulp, and masseter nerve. Antidromic activation techniques were also used to determine if the functionally identified neurons projected directly to the contralateral posterior thalamus, ipsilateral cerebellum, or cervical spinal cord. In addition, the periaqueductal gray matter (PAG) was stimulated to test for conditioning influences from the PAG on orthodromic responses to noxious and nonnoxious oral-facial stimuli. Interpolaris neurons were somatotopically arranged in subnucleus interpolaris in a pattern conforming in general to the medially facing, inverted-head representation characteristic of other parts of the V brain stem sensory nuclear complex. On the basis of their responsiveness to cutaneous stimuli, the neurons could be functionally classified as either cutaneous nociceptive or low-threshold mechanoreceptive (LTM) neurons. The LTM neurons constituted the major neuron type, accounting for over 75% of our neuron sample. Most of them had a localized mechanoreceptive field of less than 100 mm2 in area that was restricted to one V division, and they had skin-evoked response latencies indicative of afferent input predominantly from A-beta cutaneous afferents. A population of nociceptive neurons was also encountered in the lateral, marginal region of interpolaris and at its medial or ventral border with the reticular formation. These neurons were of two types: nociceptive-specific (NS) neurons, which did not respond to nonnoxious stimuli but which required noxious stimuli for their activation; and wide dynamic range ( WDR ) neurons, which responded to both noxious and nonnoxious stimuli applied to the facial skin. Most had an ipsilateral receptive field that was greater than 100 mm2 in area and that often involved two or three V divisions. Their properties generally conformed to those previously described for nociceptive neurons in the medullary dorsal horn (V subnucleus caudalis) and spinal cord dorsal horn. Interpolaris neurons of all classes (LTM, WDR , and NS) were found to have direct axonal projections to the thalamus, cerebellum, and spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)