Primate Spinothalamic Tract Neurons Research Articles

Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate

Itch of peripheral origin requires information transfer from the spinal cord to the brain for perception. Here, primate spinothalamic tract (STT) neurons from lumbar spinal cord were functionally characterized by in vivo electrophysiology to determine the role of these cells in the transmission of pruriceptive information. One hundred eleven STT neurons were identified by antidromic stimulation and then recorded while histamine and cowhage (a nonhistaminergic pruritogen) were sequentially applied to the cutaneous receptive field of each cell. Twenty percent of STT neurons responded to histamine, 13% responded to cowhage, and 2% responded to both. All pruriceptive STT neurons were mechanically sensitive and additionally responded to heat, intradermal capsaicin, or both. STT neurons located in the superficial dorsal horn responded with greater discharge and longer duration to pruritogens than STT neurons located in the deep dorsal horn. Pruriceptive STT neurons discharged in a bursting pattern in response to the activating pruritogen and to capsaicin. Microantidromic mapping was used to determine the zone of termination for pruriceptive STT axons within the thalamus. Axons from histamine-responsive and cowhage-responsive STT neurons terminated in several thalamic nuclei including the ventral posterior lateral, ventral posterior inferior, and posterior nuclei. Axons from cowhage-responsive neurons were additionally found to terminate in the suprageniculate and medial geniculate nuclei. Histamine-responsive STT neurons were sensitized to gentle stroking of the receptive field after the response to histamine, suggesting a spinal mechanism for alloknesis. The results show that pruriceptive information is encoded by polymodal STT neurons in histaminergic or nonhistaminergic pathways and transmitted to the ventrobasal complex and posterior thalamus in primates.

Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons

Itch is relieved by scratching, but the neural mechanisms that are responsible for this are unknown. Spinothalamic tract (STT) neurons respond to itch-producing agents and transmit pruritic information to the brain. We observed that scratching the cutaneous receptive field of primate STT neurons produced inhibition during histamine-evoked activity but not during spontaneous activity or activity evoked by a painful stimulus, suggesting that scratching inhibits the transmission of itch in the spinal cord in a state-dependent manner.

The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons

Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. We examined the responses of spinothalamic tract neurons to histaminergic and, for the first time, nonhistaminergic forms of itch stimuli. Fifty-seven primate spinothalamic tract (STT) neurons were identified using antidromic activation techniques and examined for their responses to histamine and cowhage, the nonhistaminergic itch-producing spicules covering the pod of the legume Mucuna pruriens. Each examined neuron had a receptive field on the hairy skin of the hindlimb and responded to noxious mechanical stimulation. STT neurons were tested with both pruritogens applied in a random order and we found 12 that responded to histamine and seven to cowhage. Each pruritogen-responsive STT neuron was activated by the chemical algogen capsaicin and two-thirds responded to noxious heat stimuli, demonstrating that these neurons convey chemical, thermal, and mechanical nociceptive information as well. Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage.

Effects of protein kinase a activation on the responses of primate spinothalamic tract neurons to mechanical stimuli.

Behavioral and anatomical studies by our group have suggested that the protein kinase A (PKA) signal transduction cascade contributes to long-term changes in nociceptive processing at the spinal cord level. In this study, we have examined the effects of activation of the PKA cascade on the responses of spinothalamic tract (STT) neurons to peripheral mechanical stimuli in anesthetized and paralyzed monkeys. PKA in the spinal cord was activated by intra-spinal infusion of forskolin, an activator of adenylate cyclase, by microdialysis. There was a consistent increase in responses to mechanical pressure and pinch stimuli in all STT cells tested when forskolin was administered. Enhanced responses remained at relatively high levels when forskolin had been washed out for 30 min. However, in most STT cells tested (65%), the responses to brushing stimuli were not obviously changed when forskolin was given. Background activity was slightly increased when forskolin was administered. An inactive isomer of forskolin, D-forskolin, did not produce significant effects on cellular activity. The sensitization of STT cells to noxious mechanical stimuli produced by forskolin could be blocked by pretreatment of the spinal cord with the PKA inhibitor, N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamine (H89). The same dose of H89 did not affect the enhanced responses to mechanical stimuli produced by activation of protein kinase G by intra-spinal infusion of 8-bromo-cGMP, indicating that the effect of forskolin was selective. The present data suggest that activation of PKA can preferentially enhance the responses of STT cells to noxious mechanical stimuli without producing an increase in responses to innocuous brushing stimuli. We speculate that the PKA signal transduction cascade may contribute more to secondary mechanical hyperalgesia than to secondary mechanical allodynia.

Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments.

Noxious stimulation of spinal afferents inhibits primate spinothalamic tract (STT) neurons in segments distant from the region of afferent entry. Inhibitory effects of cardiopulmonary sympathetic afferent (CPSA) stimulation remain after C(1) transection but disappear with spinal transection between C(3) and C(7). We hypothesized that spinal inhibitory effects produced by CPSA stimulation are processed by neurons in C(1)-C(3) segments. One purpose of this study in anesthetized monkeys was to determine whether chemical activation of high cervical neurons reduced sacral STT cell responses to colorectal distension (CRD) and urinary bladder distension (UBD). First, effects and interactions of pelvic and cardiopulmonary visceral afferent inputs were determined in 10 monkeys on extracellular activity of sacral STT neurons recorded in deep dorsal horn. CRD and UBD increased activity in 95 and 91% of sacral STT neurons, respectively. CPSA and cardiopulmonary vagal stimulation decreased activity in 84 and 56% of STT neurons, respectively. CPSA stimulation decreased CRD-evoked activity in six of eight sacral STT neurons and decreased UBD-evoked activity in five of eight STT neurons tested. Excitatory amino acid application at C2 segment decreased CRD-evoked responses in 7 of 10 sacral STT neurons and decreased UBD-evoked responses in 9 of 12 STT neurons. The second purpose of this study was to examine responses of C(1)-C(3) descending propriospinal neurons to stimulation of cardiopulmonary afferent fibers. If C(1)-C(3) neurons process CPSA input to suppress STT transmission, then CPSA stimulation should excite C(1)-C(3) neurons with descending projections. Effects of thoracic vagus nerve stimulation also were examined. Vagal stimulation inhibits STT neurons in segments below C(3) but excites C(1)-C(3) STT neurons; we theorized that vagal inhibition of sensory transmission might relay in high cervical segments and, therefore, excite C(1)-C(3) descending propriospinal neurons. Extracellular discharge rate was recorded for C(1)-C(3) neurons antidromically activated from thoracic or lumbar spinal cord in 24 monkeys. CPSA stimulation increased activity of 16 of 45 neurons and inhibited one cell. Thoracic vagus stimulation increased activity of 20 of 43 neurons and inhibited one cell; stimulation of abdominal vagus fibers did not affect activity of six of six cells that were excited by thoracic vagal input. Mechanical stimulation of somatic fields excited 30 of 41 neurons tested. All neurons activated by visceral input received convergent somatic input from noxious pinch of somatic receptive fields that generally included the neck and upper body; 11 C(1)-C(3) propriospinal neurons did not respond to any afferent input examined. Results of these studies were consistent with the idea that modulation of spinal nociceptive transmission might involve neuronal connections in high cervical segments.

Intrathecal drug therapy for chronic pain: from basic science to clinical practice.

Intrathecal drug therapy for chronic pain: from basic science to clinical practice.

Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons.

Nitric oxide (NO) has been proposed to contribute to the development of hyperalgesia by activating the NO/guanosine 3',5'-cyclic monophosphate (cGMP) signal transduction pathway in the spinal cord. We have examined the effects of NO on the responses of primate spinothalamic tract (STT) neurons to peripheral cutaneous stimuli and on the sensitization of STT cells following intradermal injection of capsaicin. The NO level within the spinal dorsal horn was increased by microdialysis of a NO donor, 3-morpholinosydnonimine (SIN-1). SIN-1 enhanced the responses of STT cells to both weak and strong mechanical stimulation of the skin. This effect was preferentially on deep wide dynamic range STT neurons. The responses of none of the neurons tested to noxious heat stimuli were significantly changed when SIN-1 was administered. Intradermal injection of capsaicin increased dramatically the content of NO metabolites, NO-2/NO-3, within the dorsal horn. This effect was attenuated by pretreatment of the spinal cord with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Sensitization of STT cells induced by intradermal injection of capsaicin was also prevented by pretreatment of the dorsal horn with the NOS inhibitors, L-NAME or 7-nitroindazole. Blockade of NOS did not significantly affect the responses of STT cells to peripheral stimulation in the absence of capsaicin injection. The data suggest that NO contributes to the development and maintenance of central sensitization of STT cells and the resultant mechanical hyperalgesia and allodynia after peripheral tissue damage or inflammation. NO seems to play little role in signaling peripheral stimuli under physiological conditions.

Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.

Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.

Nitric oxide-mediated spinal disinhibition contributes to the sensitization of primate spinothalamic tract neurons.

This study concentrated on whether an increase in spinal nitric oxide (NO) diminishes inhibition of spinothalamic tract (STT) cells induced by activating the periaqueductal gray (PAG) or spinal glycinergic and GABAergic receptors, thus contributing to the sensitization of STT neurons. A reduction in inhibition of the responses to cutaneous mechanical stimuli induced by PAG stimulation was seen in wide dynamic range (WDR) STT cells located in the deep layers of the dorsal horn when these neurons were sensitized during administration of a NO donor, 3-morpholinosydnonimine (SIN-1), into the dorsal horn by microdialysis. In contrast, PAG-induced inhibition of the responses of high-threshold (HT) and superficial WDR STT cells was not significantly changed by spinal infusion of SIN-1. A reduction in PAG inhibition when STT cells were sensitized after intradermal injection of capsaicin could be nearly completely blocked by pretreatment of the dorsal horn with a NO synthase inhibitor, 7-nitroindazole. Moreover, spinal inhibition of nociceptive activity of deep WDR STT neurons elicited by iontophoretic release of glycine and GABA agonists was attenuated by administration of SIN-1. This change paralleled the change in PAG-induced inhibition. However, the inhibition of HT and superficial WDR cells induced by glycine and GABA release did not show a significant change when SIN-1 was administered spinally. Combined with our recent results, these data show that the effectiveness of spinal inhibition can be reduced by the NO/cGMP pathway. Thus disinhibition may constitute one mechanism underlying central sensitization.

Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is reduced during central sensitization.

1. In our previous work, we demonstrated that the glycinergic and GABAergic mechanisms that help mediate the descending inhibition from the periaqueductal gray exert a tonic modulation of nociceptive inputs through spinal glycine and gamma-aminobutyric acid (GABA) receptors. This study was designed to examine further possible changes in the inhibition of the activity of spinothalamic tract (STT) neurons mediated by spinal glycine and GABA receptors when STT cells are sensitized by intradermal injection of capsaicin, and to investigate the role of the protein kinase C (PKC) system in the functional modulation of these receptors. 2. Although the responses of STT cells to cutaneous mechanical stimuli were sensitized by intradermal injection of capsaicin, the inhibition of the responses of all STT cells tested to noxious cutaneous stimuli produced by iontophoretic release of glycine and GABA was significantly attenuated. The inhibition elicited by iontophoretic application of a GABAA agonist, muscimol, was reduced in some of the cells tested. 3. When the spinal cord dorsal horn was pretreated with a selective PKC inhibitor, 2,6-diamino-N-([1-oxotridecyl-2-piperidinyl]- methyl)hexanamide, by microdialysis, sensitization of STT cells by capsaicin injection and the accompanying attenuation of glycine- and GABA-induced inhibition were prevented. 4. Sensitization of STT cells to cutaneous mechanical stimuli was also induced by administration of the PKC activator, 12-O-tetradecanoylphorbol-13-acetate, into the spinal dorsal horn. The inhibition produced by iontophoretic release of glycine, GABA, and muscimol was found to be reduced in most cells examined when this phorbol ester was used. An inactive phorbol ester, 4 alpha-phorbol 12,13-didecanoate, did not produce significant effects on cellular activity. 5. These results suggest that there is an activation of PKC in the spinal cord when STT neurons are sensitized after intradermal injection of capsaicin or administration of phorbol ester. This sensitization is likely to be involved in the development of allodynia and secondary hyperalgesia not only by enhancing the responses of excitatory amino acid receptors but also by desensitizing glycine and GABA receptors.

Possible Role of Protein Kinase C in the Sensitization of Primate Spinothalamic Tract Neurons

The responsiveness of spinal cord nociceptive neurons to innocuous mechanical stimuli can be increased by the release of excitatory amino acids (EAAs) and peptides attributable to an injury-induced barrage of impulses. This sensitization of spinal dorsal horn neurons can also result from administration of phorbol ester by microdialysis, presumably by direct activation of protein kinase C (PKC). This study was designed to examine the effects of central sensitization of spinothalamic tract (STT) neurons produced by intradermal injection of capsaicin on the descending inhibition driven from the periaqueductal gray (PAG) and the possible role of PKC in this process in anesthetized monkeys. Sensitization of responses of STT cells to mechanical stimuli was induced by intradermal injection of capsaicin. PAG inhibition was significantly attenuated when sensitization of responses to mechanical stimuli occurred. However, perfusion of the spinal cord with NPC15437 (a selective PKC inhibitor) by microdialysis could prevent the sensitization of the responses to mechanical stimuli and the reduction in PAG inhibition of these responses induced by capsaicin injection. Results similar to those produced by capsaicin injection were observed when a PKC activator, phorbol ester (12-O-tetradecanoylphorbol-13-acetate), was infused within the dorsal horn by microdialysis. An inactive phorbol ester (4 alpha-phorbol 12,13-didecanoate) had no effect. These results provide evidence that the activation of PKC contributes to the development of central sensitization in dorsal horn neurons produced by chemical stimulation with capsaicin. Attenuation of the effectiveness of PAG inhibition takes place when the sensitization of dorsal horn cells develops, and PKC may play a significant role in this process.

Chapter 12 Cooperative mechanisms of neurotransmitter action in central nervous sensitization

This chapter focuses on the mechanisms of central sensitization of nociceptive pathways using two animal models—intradermal injection of capsaicin and induction of acute arthritis. It also explores the possibility of provoking sensitization more directly by administering drugs into the dorsal horn, either by iontophoresis or by microdialysis. Central sensitization is characterized in the experiments by the following—(1) changes in the responses of primate spinothalamic tract (STT) neurons to stimulation of the skin, including increased responses to innocuous and marginally noxious stimuli and an enlarged receptive field; (2) behavioral responses to stimulation of the skin in rats indicative of allodynia and/or hyperalgesia; (3) morphological alterations in the dorsal horn in rats and monkeys; and (4) release of neurotransmitters into the dorsal horn, as determined by microdialysis and high performance liquid chromatography (HPLC) in rats and monkeys. Evidence that sensitization of central neurons can occur for periods of up to a few hours without maintained peripheral input comes from both in vivo and in vitro experiments.

Role of GABA receptor subtypes in inhibition of primate spinothalamic tract neurons: difference between spinal and periaqueductal gray inhibition.

1. gamma-Aminobutyric acid (GABA) is thought to inhibit both pre- and postsynaptically the transfer of nociceptive signals from primary afferent fibers to spinal dorsal horn sensory cells, including spinothalamic tract (STT) neurons. The inhibition can be mediated by both GABAA and GABAB receptors. We now attempt to characterize the synaptic inhibition of STT cells by spinal GABAA and GABAB receptors in anesthetized monkeys and to analyze the roles of these two receptor subtypes in the inhibition of STT cellular activity produced by stimulation in the periaqueductal gray (PAG). 2. Iontophoretic release of GABA or muscimol (a selective GABAA receptor agonist) onto STT cells elicited a profound and dose-related inhibition of the responses of all cells tested to noxious cutaneous stimuli. Only four cells (16.7%) were found to be inhibited when baclofen (a selective GABAB receptor agonist) was applied iontophoretically. However, a strong and dose-dependent inhibition of the responses to cutaneous mechanical and thermal stimuli was obtained in all cells examined when baclofen was administered into the dorsal horn through a microdialysis fiber. The inhibitory effects were mainly on nociceptive inputs. 3. The inhibition of cellular activity by GABAA and GABAB agonists could be selectively antagonized by specific antagonists applied through a microdialysis fiber. 4. The excitatory responses evoked by pulsed release of glutamic acid (GLUT) were also inhibited in a dose-related manner by iontophoretic application of GABA and muscimol, but not by baclofen. A high dose of baclofen administered by microdialysis resulted in only a small decrease in GLUT-evoked excitatory responses. 5. Infusion of GABAA and GABAB antagonists into the dorsal horn by microdialysis caused an increase in both background activity and responses to cutaneous stimuli, suggesting that there is a tonic GABAergic inhibition of STT cells. 6. The inhibition of responses to mechanical and thermal stimulation of the cutaneous excitatory receptive field resulting from stimulation in PAG was significantly antagonized in most of the STT cells tested when the GABAA antagonist bicuculline was infused into the spinal dorsal horn through a microdialysis fiber. In contrast, the inhibition produced by PAG stimulation in most of the cells examined was not significantly antagonized by the GABAB antagonists phaclofen or 3-amino-propyl(diethoxymethyl)phophinic acid (CGP35348) administered into the spinal dorsal horn by microdialysis. 7. Our results support the contention that GABAergic mechanisms in the spinal dorsal horn normally exert a tonic modulation of nociceptive inputs through both GABAA and GABAB receptors. The evidence provided here indicates that GABAA receptors located on primate STT neurons contribute to a postsynaptic inhibitory effect on the transmission of peripheral nociceptive inputs. A possible presynaptic GABAA action was not investigated. Our finding of a GABAB-receptor-mediated inhibition is consistent with the view that both pre- and postsynaptic GABAB receptors are involved in inhibitory modulation of spinal nociceptive transmission. Finally, it is suggested from this study that primate spinal GABAA, but not GABAB receptors, are involved in mediating the descending inhibition induced by PAG stimulation.

Infusion of substance P or neurokinin A by microdialysis alters responses of primate spinothalamic tract neurons to cutaneous stimuli and to iontophoretically released excitatory amino acids

The responses of 25 spinothalamic tract (STT) neurons to mechanical and thermal stimulation of the skin, as well as to a battery of iontophoretically applied excitatory amino acids (EAAs), were tested before and then during microdialysis of substance P (SP) or neurokinin A (NKA) into the dorsal horn of anesthetized monkeys. Neither peptide had significant effects on the background activity or the responses to mechanical or thermal stimulation of the skin. However, each peptide produced significant increases in the responses to iontophoretic application of one or more EAAs. In addition, following combined application of the EAAs and either SP or NKA, the responses of the cells to mechanical stimulation of the skin increased. Combined application of SP and NKA failed to produce an increase in responses to either the EAAs or to cutaneous stimuli that was greater than that produced by either peptide alone. It is concluded that SP and NKA produce an increase in the responses of STT cells to iontophoretic applications of EAAs and the combined effects of these compounds produce sustained increases in responses to mechanical stimulation of the skin. These changes mimic those observed when STT cells are sensitized by peripheral noxious stimuli, suggesting that the mechanism of induction and expression of sensitization involves the facilitation of dorsal horn neuron responses to EAAs by tachykinins.

Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin

1. Activation of neurokinin receptors contributes to the excitation of many dorsal horn neurons by cutaneous sensory stimuli, particularly noxious stimuli. In the present study we investigate the role of neurokinin receptors in the activation of primate spinothalamic tract (STT) neurons by cutaneous mechanical stimuli and by intradermal injection of capsaicin. This was done by testing the responses of these neurons to a battery of cutaneous stimuli before and during infusion by microdialysis of antagonists selective for NK1 and NK2 receptors. 2. The NK1 receptor antagonists cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine (CP96345) and D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11) (GR82334) did not significantly reduce the responses of STT cells to mechanical stimulation of the skin. Both NK1 antagonists did, however, produce a significant reduction in the responses of STT neurons to an intradermal injection of capsaicin. Finally, despite having no effects on responses to mechanical stimuli, both NK1 antagonists prevented the sensitization of the responses to cutaneous stimuli that is usually observed after intradermal injections of capsaicin. 3. The NK2 selective antagonists PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (GR98400) and [Tyr5,D-Trp6,8,9,Lys10]-NKA (4-10) (MEN10376) had effects very similar to those of the NK1 antagonists, but with an important difference. Neither NK2 antagonist affected the responses of STT neurons to noxious or innocuous mechanical stimulation of the skin, but they did reduce the responses to intradermal capsaicin injections. These compounds failed to prevent capsaicin-induced sensitization. In fact, cells exposed to GR98400 or MEN10376 showed unusually sustained increases in the responses to mechanical stimuli after the first capsaicin injection, suggesting that these compounds actually induced sensitization. 4. These results support the contention that both neurokinin receptors participate in the processing of nociceptive information in the dorsal horn, especially responses to strong stimuli such as intradermal injection of capsaicin. NK1 receptors are also involved in the sensitization of STT neurons after peripheral injury. A clearer understanding of the role of NK2 receptors in sensitization requires further studies with improved antagonists.

The role of the spinothalamic tract in the plastic changes in somatosensory thalamus and cortex caused by inflammation

Dr. Guilbaud describes 15 years of work in her laboratory in which she and her colleagues examined plastic changes in the responses of neurons in the rat somatosensory thalamus and cerebral cortex following the induction of an inflammatory pain state, either by injection of Freund's adjuvant into the tail or of carrageenan into the hindpaw. The goals of this work included: a demonstration of changes in neural responses that parallel the development of hyperalgesia and allodynia in the inflamed area; a description of changes in response to stimulation of uninflamed areas that might help explain secondary hyperalgesia; investigation of the question of whether a specific joint pain system exists; and exploration of how altered joint input might dominate cortical responses atthe expense of other somatic inputs. I will elaborate on the first three of these from the perspective of experiments on primate spinothalamic tract neurons in my laboratory.

Glycine and GABA A antagonists reduce the inhibition of primate spinothalamic tract neurons produced by stimulation in periaqueductal gray

Amino acids are demonstrated to be important neurotransmitters mediating the inhibitory transmission from nucleus raphe magnus to spinal nociceptive dorsal horn neurons. In this study, the role of glycine and GABA in the inhibitory processes evoked by stimulation in periaqueductal gray (PAG) of responses of primate spinothalamic tract (STT) neurons to cutaneous mechanical and thermal stimuli was investigated by examining the effects of strychnine and bicuculline, antagonists of glycine and GABA A receptors, respectively, introduced into the dorsal horn through a microdialysis fiber. The inhibitory effects of iontophoretic application of glycine and GABA A agonists on STT cell activity evoked by noxious mechanical stimulation of the skin were selectively blocked by their specific antagonist, strychnine or bicuculline, infused into the dorsal horn. Similarly, intra-spinal application of strychnine or bicuculline resulted in a significant reduction in the PAG stimulation-induced inhibition of responses of STT cells to cutaneous stimuli. This reduction was mainly on the PAG-induced inhibition of the responses to noxious mechanical stimuli. Our results suggest that glycinergic and GABAergic inhibitory interneurons in the spinal cord dorsal horn synapsing on STT cells are activated during stimulation in PAG and contribute to descending antinociceptive actions.

The effect of trans-ACPD, a metabotropic excitatory amino acid receptor agonist, on the responses of primate spinothalamic tract neurons

The responses of primate spinothalamic tract (STT) neurons to innocuous and noxious mechanical stimuli applied to the skin can be enhanced for more than an hour following prolonged noxious stimulation. This increased responsiveness is thought to reflect sensitization of dorsal horn neurons and may help account for secondary hyperalgesia and mechanical allodynia. The proposal that central sensitization is due to the activation of second messenger systems was tested in this study by examining the effect of trans-ACPD ( trans- d,l-1-amino-1, 3-cyclopentanedicarboxylic acid), an agonist of metabotropic excitatory amino acid (EAA) receptors, introduced into the dorsal horn by microdialysis. A low dose of trans-ACPD resulted in an increase in the responses of STT cells to an innocuous mechanical stimulus (BRUSH), but no increase in the responses to noxious mechanical and thermal stimuli or in the excitation produced by iontophoretically applied EAAs. A high dose of trans-ACPD caused a transient increase in background activity, but no change in the responsiveness of spinothalamic cells to any of the test stimuli. It is concluded that low doses of trans-ACPD can selectively enhance transmission through interneuronal pathways mediating tactile inputs to spinothalamic cells.

The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli

The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

Evidence that C1 and C2 propriospinal neurons mediate the inhibitory effects of viscerosomatic spinal afferent input on primate spinothalamic tract neurons.

1. Lumbosacral spinothalamic tract (STT) neurons can be inhibited by noxious pinch of the contralateral hindlimb or either forelimb and by electrical stimulation of cardiopulmonary sympathetic, splanchnic, and hypogastric afferents. A previous study found that spinal transections between C2 and C4 sometimes abolished the inhibitory effect of spinal afferent input and sometimes left it intact. This suggested that propriospinal neurons in the C1 and C2 segments might mediate this effect. To test whether neurons in the C1 and C2 segments were involved in producing this inhibitory effect, the magnitude of the reduction in neural activity was measured in the same STT neuron before and after spinal transection at C1 or between C3 and C7. 2. All neurons were antidromically activated from the contralateral thalamus and thoracic spinal cord. For us to accept a neuron for analysis, the characteristics of the somatic input and the latency and shape of the antidromatic spike produced by spinal cord stimulation had to be the same before and after the spinal transection. Also, spinal transection often causes a marked increase in spontaneous cell activity, which may affect the magnitude of an inhibitory response. To avoid this confounding problem, a cell was accepted for analysis only if it showed marked inhibition of high cell activity evoked by somatic pinch before spinal transection. For analysis 13 STT neurons met these criteria: 6 neurons were in monkeys with C1 transections, and 7 neurons were in animals with transections between C3 and C7.(ABSTRACT TRUNCATED AT 250 WORDS)