Different classes of cat spinal neurons display differential sensitivity to sodium pentobarbital

The effect of graded doses of systemically injected sodium pentobarbital on several classes of spinal neurons was studied using spinal cats. Classes of spinal neurons included unidentified dorsal horn cells, ascending tract dorsal horn cells, and motoneurons. Single unit activity of spinal neurons was evoked by electrically stimulating a peripheral nerve with an intensity strong enough to excite both A and C fibers. The A- and C-fiber evoked activity was compared before and after intravenous injections of small incremental doses of sodium pentobarbital. The activity of different classes of spinal neurons showed different sensitivities to graded doses of systemically injected pentobarbital. The reflex activity of motoneurons elicited by stimulation of peripheral nerve was much more sensitive to pentobarbital than that of dorsal horn cells. In general, activity evoked by peripheral unmyelinated fibers was more susceptible to pentobarbital than was that evoked by myelinated fibers. However, intravenous injections of pentobarbital produced nondifferential suppression of dorsal horn cell activity evoked by noxious and innocuous mechanical stimuli applied to the peripheral receptive fields.     

Chronic Spinal Nerve Ligation Induces Changes in Response Characteristics of Nociceptive Spinal Dorsal Horn Neurons and in Their Descending Regulation Originating in the Periaqueductal Gray in the Rat

We studied whether a chronic neuropathy induced by unilateral spinal nerve ligation changes the response characteristics of spinal dorsal horn wide-dynamic range (WDR) neurons or their periaqueductal gray (PAG)-induced descending modulation. Experiments were performed in rats with behaviorally demonstrated allodynia induced by spinal nerve ligation and in a group of nonneuropathic control rats. The stimulus–response functions of WDR neurons for mechanical and thermal stimuli and the modulation of their peripherally evoked responses by electrical stimulation of the PAG were determined under pentobarbital anesthesia. The results showed that neuropathy caused a significant leftward shift in stimulus–response functions for mechanical stimuli. In contrast, stimulus–response functions for noxious heat stimuli in the neuropathic limb were, if anything, shifted rightward, although this shift was short of statistical significance. In neuropathic rats, PAG stimulation produced a significantly stronger attenuation of spinal neuronal responses induced by noxious heat in the unoperated than in the operated side. At the intensity that produced attenuation of noxious heat stimuli, PAG stimulation did not produce any significant change in spinal neuronal responses evoked by mechanical stimuli either from the operated or the nonoperated hindlimb of the neuropathic rats. Spontaneous activity of WDR neurons was higher in the operated side of neuropathic rats than in control rats. Afterdischarges evoked by peripheral stimuli were observed in 1/16 of the WDR neurons ipsilateral to spinal nerve ligation and not at all in other experimental groups. The WDR neurons studied were not activated by innocuous or noxious cold stimuli. The results indicate that spinal nerve ligation induces increased spontaneous activity and enhanced responses to mechanical stimuli in the spinal dorsal horn WDR neurons, whereas noxious heat-evoked responses are not significantly changed or if anything, attenuated. Moreover, the inhibition of noxious heat stimuli by PAG stimulation is attenuated in the neuropathic side. It is proposed that the observed changes in the response characteristics of the spinal dorsal horn WDR neurons and in their descending modulation may contribute to the neuropathic symptoms in these animals.     

Spinal antinociception mediated by a cocaine-sensitive dopaminergic supraspinal mechanism

The role of dopaminergic descending supraspinal processes in mediating the antinociceptive action of cocaine was studied in the rat using a combination of extracellular neuronal recording and behavioral techniques. Neurons in the superficial laminae (I-II) of the spinal dorsal horn with receptive fields on the tail were recorded in anesthetized rats using insulated metal microelectrodes. Stimulation of the receptive field with either high intensity transcutaneous electrical pulses or with an infrared CO₂ laser beam produced a biphasic increase in dorsal horn unit discharge. Conduction velocity estimates indicated that the early discharge corresponded to activity in Aδ whereas the late response corresponded to activity in C afferent fibers. Cumulative doses of cocaine (0.1–3.1 mg/kg i.v.) inhibited the late response to either electrical or laser stimulation in a dose-related manner. The early response to laser, but not electrical, stimulation was also suppressed by cocaine. Neurons in the spinal dorsal horn with receptive fields on the ipsilateral hindpaw were activated by natural noxious (pinch) or innocuous (tap) somatic stimulation. Cocaine selectively suppressed nociceptively evoked dorsal horn unit discharge. This antinociceptive effect was dose-related (0.3–3.1 mg/kg, i.v.) and antagonized by eticlopride (0.05–0.1 mg/kg, i.v.), a selective D2 dopamine receptor blocker. The same doses of cocaine failed to inhibit the responses of dorsal horn neurons to low threshold innocuous stimulation. Complete thoracic spinal cord transection eliminated the antinociceptive effect of cocaine on dorsal horn neurons and also eliminated the cocaine-induced attenuation of the tail-flick reflex. These data demonstrte that cocaine selectively inhibits nociceptive spinal reflexes and the nociceptive responses of dorsal horn neurons primarily by means of a D2 dopaminergic receptor mechanism. This antinociceptive effect of cocaine is independent of its local anesthetic activity and requires the integrity of the thoracic spinal cord, suggesting that the drug potentiates or activates supraspinal dopaminergic projections to the dorsal horn.     

Nonsegmental inhibition of rat dorsal horn neurons by innocuous stimulation

In rats anesthetized with thiamylal sodium, responses of spinal cord dorsal horn neurons to noxious skin heating of the tail were recorded by extracellular microelectrodes. Inhibition of these responses by innocuous mechanical stimulation (light brushing) of the ipsilateral forelimb was assessed. Short-lasting application (3 min, or less) of light brushing did not inhibit neuronal responses to noxious heating. Long-lasting application (5 min, or more) inhibited responses of these neurons to noxious stimulation. The results indicate that, in the anesthetized rat, remotely applied innocuous cutaneous stimuli can inhibit nociceptive responses of dorsal horn neurons, if applied for a sufficiently long time.     

Effects of selective and non-selective -opioid receptor agonists on cutaneous C-fibre-evoked responses of rat dorsal horn neurones

We have studied the effects of 3 putative kappa-opioid receptor agonists, U50488H, ethylketocyclazocine (EKC) and dynorphin A1-13 (DYN) on the processing of nociceptive information in the dorsal horn of the rat under halothane anaesthesia. Extracellular single unit recordings were made from convergent or multireceptive lumbar dorsal horn neurones, which could be excited by impulses in A beta and C fibre afferents following transcutaneous electrical stimulation of their ipsilateral hind paw receptive fields and also by noxious and innocuous natural stimuli. Agonists were applied directly onto the surface of the spinal cord. DYN and U50488H consistently produced both a facilitation and inhibition of the C-fibre evoked nociceptive responses of individual cells, these dual effects being relatively insensitive to naloxone antagonism and cancelled each other for the whole population of cells. A beta fibre-evoked responses were little altered. In contrast, EKC consistently depressed C-fibre transmission in a dose-dependent, naloxone reversible manner, analogous to, but considerably less potent than intrathecal morphine under identical experimental conditions. Agonist-induced effects on neuronal responses to natural stimulation (noxious pinch and innocuous prod) were consistent with the changes observed with the electrically evoked responses. The present results therefore indicate that EKC probably exerts its spinal antinociceptive activity in the rat spinal cord in a manner akin to mu-receptor activation. Results with U50488H and DYN indicate that -opioids can excite and inhibit individual neurones but produce no overall change on the whole population, so differing from effects mediated by the other opiate receptors.     

Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex

Motor cortex stimulation (MCS) has been used clinically as a tool for the control for central post-stroke pain and neuropathic facial pain. The underlying mechanisms involved in the antinociceptive effect of MCS are not clearly understood. We hypothesize that the antinociceptive effect is through the modulation of the spinal dorsal horn neuron activity. Thirty-two wide dynamic range spinal dorsal horn neurons were recorded, in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields, while a stepwise electrical stimulation was applied simultaneously in the motor cortex. The responses to brush at control, 10 V, 20 V, and 30 V, and recovery were 11.5+/-1.6, 12.1+/-2.6, 11.1+/-2.2, 10.5+/-2.1, and 13.2+/-2.5 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, and 30 V, and recovery were 33.2+/-6.1, 22.9+/-5.3, 20.5+/-5.0, 17.3+/-3.8, and 27.0+/-4.0 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, and 30 V, and recovery were 37.2+/-6.4, 26.3+/-4.7, 25.9+/-4.7, 22.5+/-4.3, and 35.0+/-6.2 spikes/s, respectively. It is concluded that, in the rat, electrical stimulation of the motor cortex produces significant transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting their response to an innocuous stimulus.     

The effects ofL-DOPA on dorsal horn cell responses to innocuous skin stimulation

The effects ofl-DOPA on responses of dorsal horn cells to innocuous mechanical skin stimulation were studied. Following intravenous administration ofl-DOPA (10–40 mg/kg) to cats with intact spinal cords, dorsal horn cells, which could be activated by only innocuous or innocuous and noxious stimuli, demonstrated increased responses manifested by an increase in the average number of spikes per stimulus, increased receptive field size and occasional changes in adequate stimuli. When cats with acute cord transections were studied,l-DOPA increased the responses of cells located in lamina 4 and those cells which responded only to innocuous stimuli; cells which responded to noxious stimuli and those located in other laminae had depressed responses followingl-DOPA administration. The inhibitory effects ofl-DOPA were in part abolished, in spinal cats, by pretreatment with parachlorophenylalanine, a serotonin depletor. Studies of dorsal cells in chronic spinal cats indicated that the effects ofl-DOPA were largely dependent on functioning terminals of descending suprasegmental pathways. The conclusion was reached that descending noradrenergic pathways, indirectly, cause an increase in transmission from cutaneous afferents to dorsal horn cells and that some of the inhibitory effects ofl-DOPA described by others are m manifestation ofl-DOPA interactions with inhibitory serotonergic systems     

The effects of L-dopa on dorsal horn cell responses to innocuous skin stimulation.

The effects of L-DOPA on responses of dorsal horn cells to innocuous mechanical skin stimulation were studied. Following intravenous administration of L-DOPA (10--40 mg/kg) to cats with intact spinal cords, dorsal horn cells, which could be activated by only innocuous or innocuous and noxious stimuli, demonstrated increased reponses manifested by an increase in the average number of spikes per stimulus, increased receptive field size and occasional changes in adequate stimuli. When cats with acute cord transections were studied, L-DOPA increased the responses of cells located in lamina 4 and those cells which responded only to innocuous stimuli; cells which responded to noxious stimuli and those located in other laminae had depressed responses following L-DOPA administration. The inhibitory effects of L-DOPA were in part abolished, in spinal cats, by pretreatment with parachlorophenylalanine, a serotonin depletor. Studies of dorsal cells in chronic spinal cats indicated that the effects of L-DOPA were largely dependent on functioning terminals of descending suprasegmental pathways. The conclusion was reached that descending noradrenergic pathways, indirectly, cause an increase in transmission from cutaneous afferents to dorsal horn cells and that some of the inhibitory effects of L-DOPA described by others are a manifestation of L-DOPA interactions with inhibitory serotonergic systems.     

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat.

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site.     

Changes in the electrical activity of spinal cord neurons of adrenalectomized rats under the effect of adrenal cortex hormones

Effect of dexamethasone and desoxycorticosterone on the electrical activity of neurons in dorsal and ventral horn of spinal cord evoked by sciatic nerve stimulation were studied in adrenalectomized rats as well as effect of the same hormones on the background activity of single cells in the dorsal horn. The results demonstrated that both hormones (dexamethasone and desoxycorticosterone) provided enhancement of the amplitude of the field potentials recorded from the dorsal half of the spinal cord and facilitation of the background neuronal discharges of the single cells under investigation. It was stated that gluco- and mineralocorticoid hormones exerted different effects on the activity of ventral horn neurons of the spinal cord: dexamethasone++ potentiated and desoxycorticosterone depressed the amplitudes of the field potentials recorded from the region of motoneurons. The presented data have shown the modulatory effects of neurosteroids on the electrical activity of the spinal cord neurons.     

Plasticity of some spinal dorsal horn neurons as revealed by pentobarbital-induced disinhibition

Extracellular activity was recorded from single spinal dorsal horn neurons in physiologically intact, awake, drug-free cats before and after the intravenous administration of 20 mg/kg pentobarbital (Pb). Pb produced a series of changes in response properties that reflect a significant moment-to-moment plasticity of some spinal dorsal horn neurons. Pb administration unmasked the ability of some low-threshold (LT) neurons to respond to noxious mechanical or thermal stimuli resulting in their being reclassified as wide dynamic range (WDR) neurons. Pb also appeared to unmask an afterdischarge in some neurons following noxious mechanical stimulation. In addition, some neurons appeared to be better able to signal changes in the intensity of mechanical stimulation after Pb. Neuronal receptive fields for low threshold stimulation were reduced in many instances but enlargement was also observed. The responses of some neurons to peripheral stimulation were unchanged by Pb. We hypothesize that the relatively low doses of Pb used in the study reduced tonic inhibition of some spinal dorsal neurons although the observed effects could have been produced by excitation.     

An alpha 2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones

Extracellular recordings were made of 59 neurones with long, ascending projections (spinocervical tract (SCT) and dorsal column postsynaptic (DCPS) neurones) in the lumbar dorsal horn of anaesthetized and paralyzed cats. All showed prominent excitatory responses to innocuous stimuli, applied to their cutaneous receptive fields on the ipsilateral hindlimb. The majority of the population investigated (83%) was multireceptive, being activated by noxious as well as innocuous cutaneous stimuli. Drug effects were examined on a regular cycle of responses to these cutaneous stimuli and also to DL-homocysteic acid (DLH). In 49 multireceptive SCT and DCPS neurones, ionophoretically-applied L-noradrenaline (NA) produced a potent selective inhibition of the nociceptive responses (to heat or pinch) in 40 out of 44 SCT and 3 out of 5 DCPS neurones, with no statistically significant change in the responses to innocuous brush or DLH, or in spontaneous activity. NA had no effect on the majority of cells (8 out of 11) that responded only to innocuous stimuli. In 19 SCT neurones that showed NA-selectivity, the alpha 2-selective agonists clonidine (in 12 out of 15) and metaraminol (in 2 out of 3) mimicked this selective effect, whereas, the alpha 1 agonist, phenylephrine and the beta agonist, isoprenaline did not. Furthermore, the alpha 2 antagonists, yohimbine and idazoxan (RX781094), either reversed or reduced the potency of the NA-elicited inhibition of nociceptive responses in all 7 SCT neurones tested. These results are discussed in relation to other evidence for spinal antinociceptive effects of noradrenergic systems acting at a spinal level and the possible involvement of an alpha 2 receptor in such effects.     

Alpha motoneuron responses to natural stimuli in decerebellate cats.

The responses of single alpha motoneurons to various "natural' stimuli were recorded from dissected ventral root filaments in lightly anesthetized control and recently decerebellate cats. The identity of the motoneurons was established by recording the unitary responses to orthodromic stimulation of nerves innervating the triceps surae muscles in the hindlimb. We recorded only the activity of units which responded to electrical stimulation of the medial or lateral gastrocnemius nerves, though some units responded to stimulation of both these nerves, and some also responded to stimulation of the posterior tibial nerve. The distributions of unit latencies and amplitudes did not differ between the two groups of animals. Baseline firing rates were also similar. However, unit firing rates in response to neck extension, ipsilateral hindfoot dorsi- or ventral-flexion were significantly higher in decerebellate than in control cats. The discharge rates in response to other stimuli, including neck flexion, pinna stimulation, and noxious stimulation in the hindlimb, were not significantly different between the two groups. Since the alpha motoneurons showed an increase in responsiveness only to some stimuli, specific mechanisms probably explain this release. The most important mechanism seems to be a loss of inhibition normally exerted by the cerebellum on vestibular and joint proprioceptive reflexes. The pathways to the ventral horn cells are thought to involve the vestibulo-spinal and reticulo-spinal tracts.     

Electrical stimulation of thalamic Nucleus Submedius inhibits responses of spinal dorsal horn neurons to colorectal distension in the rat

In 78 halothane-anesthetized rats, we characterized the responses of single neurons in the dorsal horn of L(6)-S(1) spinal segments to a noxious visceral stimulus (colorectal balloon distension, CRD), and studied the effects of focal electrical stimulation of Nucleus Submedius (Sm) on these responses using standard extracellular microelectrode recording techniques. A total of 102 neurons were isolated on the basis of spontaneous activity. Eighty (78%) responded to CRD, of which 70% had excitatory and 30% had inhibitory responses. Neurons showed graded responses to graded CRD pressures (20-100 mmHg), with maximum excitation or inhibition occurring at 100 mmHg. Responses to noxious (pinch, heat) and innocuous (brush, tap) cutaneous stimuli were studied in 73 of the spinal dorsal horn neurons isolated. Fifty-seven (78%) of these neurons (46 CRD-responsive and 11 CRD-nonresponsive) had cutaneous receptive fields, of which 35 (61%) were small and ipsilateral, 14 (25%) were large and ipsilateral, 7 (12%) were large or small and bilateral, and 1 (2%) was small and contralateral. Sixty-one percent of these neurons responded to both noxious and innocuous cutaneous stimulation, 35% responded only to noxious stimulation, and 4% responded only to innocuous stimulation. Electrical stimulation (50-300 microA) of the contralateral Sm produced intensity-dependent attenuation of the CRD-evoked activities of most neurons (18/28 of CRD-excited and 7/12 of CRD-inhibited) tested. Sm stimulation produced facilitation of CRD responses of only one neuron (CRD-inhibited). Sm stimulation had no effects on spontaneous activity. These data indicate that Sm may be involved in the descending inhibitory modulation of visceral nociception at the spinal level.     

The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain

Neuropathic pain is a difficult state to treat, characterized by alterations in sensory processing that can include allodynia (touch-evoked pain). Evidence exists for nerve damage-induced plasticity in both transmission and modulatory systems, including changes in voltage-dependent calcium channel (VDCC) expression and function; however, the role of Ca(v)2.3 calcium channels has not clearly been defined. Here, the effects of SNX-482, a selective Ca(v)2.3 antagonist, on sensory transmission at the spinal cord level have been investigated in the rat. The spinal nerve ligation (SNL) model of chronic neuropathic pain [Kim & Chung, (1992)Pain, 50, 355-363] was used to induce mechanical allodynia, as tested on the ipsilateral hindpaw. In vivo electrophysiological measurements of dorsal horn neuronal responses to innocuous and noxious electrical and natural stimuli were made after SNL and compared to sham-operated animals. Spinal SNX-482 (0.5-4 microg/50 microL) exerted dose-related inhibitions of noxious C-fibre- and Adelta-fibre-mediated neuronal responses in conditions of neuropathy, but not in sham-operated animals. Measures of spinal cord hyperexcitability and nociception were most susceptible to SNX-482. In contrast, non-noxious Abeta-mediated responses were not affected by SNX-482. Moreover, responses to innocuous mechanical and also thermal stimuli were more sensitive to SNX-482 in SNL than control animals. This study is the first to demonstrate an antinociceptive role for SNX-482-sensitive channels in dorsal horn neurons during neuropathy. These data are consistent with plasticity in Ca(V)2.3 calcium channel expression and suggest a potential selective target to reduce nociceptive transmission during conditions of nerve damage.     

Responses of spinal neurones to cutaneous and dorsal root stimuli in rats with mechanical allodynia after contusive spinal cord injury

The firing of neurones in spinal segments adjacent to a contusive T13 spinal cord injury was characterised in anaesthetised rats. Three groups of rats were examined: (1) allodynic spinally injured, (2) non-allodynic spinally injured and (3) normal, uninjured. Spinal cord field potentials evoked by electrical dorsal root stimulation and the responses of 207 dorsal horn neurones to mechanical stimuli applied to the skin were studied. Within the lesioned spinal segment few active neurones were encountered and field potentials were absent. Depolarising field potentials recorded rostral to the lesion were reduced in both allodynic and non-allodynic animals compared to uninjured controls, while those recorded in caudal segments were enhanced in allodynic animals. Neuronal recordings revealed that allodynia was associated with exaggerated responses, including afterdischarges, to innocuous and noxious mechanical stimuli in a proportion of wide dynamic range, but not low threshold, neurones. These changes were observed both rostral and caudal to the site of injury. The results suggest that an increased responsiveness of some dorsal horn neurones in segments neighbouring a contusive spinal cord injury may contribute to the expression of mechanical allodynia. It is proposed that a relative lack of inhibition underlies altered cell responses.     

Effects of capsaicin applied to a peripheral nerve on the responses of primate spinothalamic tract cells

Capsaicin is a neurotoxin that appears to affect unmyelinated nociceptive sensory fibers selectively. We examined the effects of capsaicin applied topically to the sural nerve on peripheral nerve volleys and on the responses of neurons belonging to the spinothalamic tract (STT) in the monkey. The responses examined included those following electrical stimulation of the sural nerve and also those produced by more natural forms of noxious and innocuous stimuli applied to the skin. Capsaicin (1% solution) applied onto the sural nerve for 15 min resulted in a reduction of the sizes of A delta- and C-fiber afferent volleys. These changes paralleled the reduction of A- and C-fiber responses of the STT cells elicited by electrical stimulation of the sural nerve. During capsaicin application onto the sural nerve, the background activity of STT cells increased for 5-10 min. After capsaicin treatment, the responses of STT cells to innocuous mechanical stimuli applied to the cutaneous receptive field were increased, whereas the responses to noxious mechanical stimuli were decreased. However, topical capsaicin application almost eliminated the responses of STT cells to noxious heat stimuli. The results of the present study suggest that topical capsaicin application onto a peripheral nerve produces a transient nociceptive response followed by a decrease in sensitivity to noxious stimuli, particularly to noxious heat. These changes are due to conduction block of the nerve fibers at the site of capsaicin application.     

The effect of systemic morphine upon diffuse noxious inhibitory controls (DNIC) in the rat: evidence for a lifting of certain descending inhibitory controls of dorsal horn convergent neurones

The effect of exogenous opiates upon diffuse noxious inhibitory controls (DNIC) was investigated in intact anaesthetized rats. 58 convergent neurones, responding to both noxious and innocuous stimuli applied to their cutaneous receptive fields, were recorded at the lumbar level. These cells received A- and C-peripheral fibre inputs as shown by electrical stimulation of their receptive fields and were mainly located in the medial part of the dorsal horn.The immersion of the distal two-thirds of the tail in hot water (52 °C) induced strong inhibition of the responses to both A-(23%) and C-(69%) fibres. Post-effects of long duration were commonly observed after cessation of the conditioning stimulus.While systematic injection of morphine at a low dose-range (0.1–1 mg/kg) did not significantly affect the unconditioned responses, the DNIC-mediated inhibitions were profoundly altered.(a) DNIC of responses to C fibres were dose-dependently (P < 0.01) lifted by morphine: (b) the post-effects observed after cessation of conditioning stimuli were dose-dependently (P < 0.01) diminished; (c) DNIC of responses to A-fibre were similarly altered but this effect was less significant (P < 0.05); (d) DNIC of responses to sustained moderate pressure were greatly diminished by morphine (P < 0.01); and (e) these effects were specific since they were antagonized by the opiate antagonist, naloxone. In addition, they were shown to be stereospecific since while the dextrogyre stereoisomer, dextrorphan, was ineffective the levogyre derivative, levorphanol, induced a significant lifting of DNIC.It is concluded that morphine decreases the supraspinal inhibitory controls of dorsal horn convergent neurones, at least when these controls are triggered by noxious stimuli. Assuming that a basic somatosensory background activity (noise) is transmitted to higher centres by dorsal horn convergent neurones, and that the pain-signalling message is the contrast between the activity of the segmental pool of neurones induced by the noxious stimulus and the DNIC-mediated silence of the remaining neuronal population, it is proposed that, by a reduction in DNIC, low-dose morphine could restore the initial level of background activity, the final result being analgesia.     

Mapping increased glycogen phosphorylase activity in dorsal root ganglia and in the spinal cord following peripheral stimuli

A histochemical technique has been used to map the distribution and the relative proportion of the active and inactive form of the enzyme glycogen phosphorylase in the primary afferent cell bodies of lumbar dorsal root ganglia and within the lumbar spinal cord of the rat. The glycogen phosphorylase was found to be present in large and small diameter primary afferent cell bodies and in the grey matter of the spinal cord, except in lamina 2. Most of the glycogen phosphorylase in control rats was in the inactive form. Peripheral innocuous mechanical and thermal stimuli failed to alter the activity of glycogen phosphorylase in the lumbar spinal cord, but noxious mechanical, chemical, and thermal stimuli when applied to the hindlimb of decerebrate rats increased the enzyme activity in the ipsilateral dorsal horn within 10 minutes. The number of primary afferent cell bodies with active glycogen phosphorylase also increased. These changes are likely to be due to the conversion of the inactive "b" form of the enzyme to the active "a" form under the influence of a calcium or cyclic AMP activated phosphorylase b kinase. Pentobarbitone anaesthesia diminished but did not completely suppress the noxious stimulus-evoked glycogen phosphorylase activity changes. Graded electrical stimulation of the sciatic nerve was performed to simulate the effects of the peripheral noxious stimuli in a controlled fashion. Stimulation at a strength that activated only large myelinated afferents produced no greater effect on the distribution of the active form of the enzyme in the dorsal horn than that produced by exposure of the nerve, but stimulation of the thin myelinated A-delta afferents and unmyelinated C-fibres produced a widespread increase in glycogen phosphorylase activity in the spinal cord and in the L4 dorsal root ganglion. The increased activity could be detected after stimulation for as short a period of time as 5 minutes. The mechanisms underlying the stimulus-evoked increase in glycogen phosphorylase activity in the spinal cord and dorsal root ganglia are not yet known, nor have we positively established which elements in the spinal cord, neurones, or glia are responsible for the changes in the glycogen phosphorylase activity. Nevertheless, it is clear that the neural activity generated by certain types of high threshold input is associated with the activation of glycogen phosphorylase, and this may be a useful tool for studying the spatial distribution of some activity-related changes in the nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)     

Thalamic nucleus ventro-postero-lateralis inhibits nucleus Parafascicularis response to noxious stimuli through a non-opioid pathway

These experiments investigated the role of a specific thalamic nucleus in the cellular response to noxious and non-noxious inputs. Single-unit extracellular responses to peripheral noxious stimuli were recorded with glass micropipettes in the nucleus parafascicularis (Pf) of the rat under chloral hydrate anesthesia. Bipolar stimmulating/recording electrodes were inserted in the nucleus ventro-posterolateralis (VPL) of the thalamus, in areas responsive to the peripheral noxious stimulation. Single-unit records in Pf and multi-unit records in VPL demonstrated that both these nuclei are differentially sensitive to noxious and non-noxious inputs: Pf was more sensitive to late (200–600 ms latency) high threshold noxious inputs, while VPL was more responsive to early (10–40 ms) low threshold non-noxious inputs. Late, high threshold inputs to VPL were selectively suppressed by systemic morphine and restored by naloxone. Trains of stimuli applied to VPL suppressed the response of 76% of Pf units, to peripheral noxious stimuli but did not inhibit the response of spinal cord dorsal horn units to the same stimuli. This inhibitory effect of VPL on Pf cells was not reversed by systemically administered naloxone. The neural pathways responsible for the VPL suppression of Pf nociception appear to be neither monosynaptic nor mediated through the spinal cord dorsal horn, nor through any single, naloxone-reversible, central opioid process. Nevertheless, this inhibitory effect of VPL stimulation on Pf nociception provides a physiological basis for the analgesic effects of thalamic stimulation on clinically observed deafferentation pain. It also supports the existence of a pain modulating system at the thalamic level comparable, at least in part, with the spinal Gate Control concept.