William D. Willis

Diencephalic mechanisms of pain sensation

‘Universite Pierre et Marie Curie (Paris VI) and Groupe de Neurobiologie Appliqute, Laboratoire de Physiologie de la Nutrition, C. N. R. 7, 78350 Jouy en Josas (France); 2Department of Psychology, Florida State University, Tallahassee, FL, 32306 (U.S.A.); 3Departments of Anatomy and Anesthesiology and Ahmanson Laboratory of Neurobiology, Brain Research Institute, UCLA Center for the Health Sciences, Los Angeles, CA, 90024 (U.S.A.); “Department of Anatomy, School of Medicine, University of California, San Fransisco, CA, 94143; and *Departments of Physiology and Biophysics and Anatomy, Marine Biomedical Institute, University of Texas Medical Branch, Galveston, TX, 77550 (U.S.A.)

Dorsal root potentials and dorsal root reflexes: a double-edged sword

 The nature of dorsal root reflexes (DRRs) and their possible role in peripheral inflammation and the consequent hyperalgesia are reviewed. The history of DRRs and the relationship of DRRs to primary afferent depolarization and presynaptic inhibition in pathways formed by both large and fine afferents are discussed. Emphasis is placed on the mechanisms underlying primary afferent depolarization, including the anatomical arrangement of the synapses involved, how depolarization can result in inhibition by decreasing transmitter release, the role of excitatory amino acids and GABA, the manner in which the equilibrium potential for chloride ions is determined in primary afferent fibers, and forms of presynaptic inhibition that do not utilize GABAA receptors. There is then a discussion of neurogenic inflammation, including the role of the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings. Evidence is reviewed that links DRRs to a substantial part of the swelling of the knee joint in acute experimental arthritis and to the flare reaction in the skin following intradermal injection of capsaicin. Possible mechanisms by which the level of DRR activity might be enhanced following inflammation are suggested. The consquences of this increase in DRRs may include exacerbation of hyperalgesia as well as of peripheral inflammation. The conversion of an inhibitory process, presynaptic inhibition, to an excitatory one by DRRs can thus lead to pathological consequences.Abstract The nature of dorsal root reflexes (DRRs) and their possible role in peripheral inflammation and the consequent hyperalgesia are reviewed. The history of DRRs and the relationship of DRRs to primary afferent depolarization and presynaptic inhibition in pathways formed by both large and fine afferents are discussed. Emphasis is placed on the mechanisms underlying primary afferent depolarization, including the anatomical arrangement of the synapses involved, how depolarization can result in inhibition by decreasing transmitter release, the role of excitatory amino acids and GABA, the manner in which the equilibrium potential for chloride ions is determined in primary afferent fibers, and forms of presynaptic inhibition that do not utilize GABAA receptors. There is then a discussion of neurogenic inflammation, including the role of the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings. Evidence is reviewed that links DRRs to a substantial part of the swelling of the knee joint in acute experimental arthritis and to the flare reaction in the skin following intradermal injection of capsaicin. Possible mechanisms by which the level of DRR activity might be enhanced following inflammation are suggested. The consquences of this increase in DRRs may include exacerbation of hyperalgesia as well as of peripheral inflammation. The conversion of an inhibitory process, presynaptic inhibition, to an excitatory one by DRRs can thus lead to pathological consequences.

Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of n-methyl-d-aspartic acid and substance P

&NA; A role for sensitization of nociceptors in the generation of primary hyperalgesia is well documented. More recent work has begun to define a role of an increased excitability of neurons within the spinal cord in the generation of secondary hyperalgesia. The present study demonstrates increased responses of primate spinothalamic neurons following co‐administration of n‐methyl‐d‐aspartic acid (NMDA) and substance P (SP) by micro‐iontophoresis. Wide dynamic range and high threshold STT neurons in laminae I‐VI showed an increased frequency of discharges following application of NMDA which was characterized by a slow onset to peak discharge rate and a slow return to background levels of discharge. Combined application of NMDA with SP resulted in an enhancement of responses to NMDA that often long outlasted the administration of SP. This increase in response of the cells to NMDA was not produced by repeated application of NMDA alone or following combined application of NMDA with an SP analog. NMDA responses were reduced or prevented in all cases by co‐application of an NMDA‐receptor antagonist. Finally, long‐lasting potentiation of NMDA responses by SP was paralleled by enhanced responses to mechanical stimulation of skin. It is proposed that a mechanism involving the combined synaptic release of excitatory amino acids and peptides leads to secondary hyperalgesia.

Role of Neurotransmitters in Sensitization of Pain Responses

Abstract: Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non‐NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long‐lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin‐dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long‐term potentiation.

Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats

The involvement of excitatory amino acid receptors in peripheral nociceptive processing was assessed in two separate experiments. In the first, one knee joint cavity of rats was injected with 0.1 ml of L-glutamate (0.001 mM; 0.1 mM; 1.0 mM), L-aspartate (0.001 mM; 0.1 mM: 1.0 mM), L-arginine (0.1 mM) or different combinations of these amino acids. The animals tested for paw withdrawal latency to radiant heat and withdrawal threshold to von Frey filaments at different time points. Combinations of glutamate/aspartate, aspartate/arginine or glutamate/aspartate/arginine when injected into the joint, in the absence of any other treatment, reduced the paw withdrawal latency and withdrawal threshold immediately after the injection and persisting up to 5 h indicating the development of hyperalgesia and allodynia. Subsequent intra-articular injection of either an NMDA or a non-NMDA glutamate receptor antagonist ((+/-)-2-amino-7-phosphonoheptanoic acid (AP7), 0.2 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 0.1 mM) attenuated the thermal hyperalgesia and the mechanical allodynia produced by glutamate/aspartate/arginine. On the other hand, in a second experiment intra-articular injection of AP7, ketamine or CNQX reversed the hyperalgesia and allodynia produced by injection of a mixture of kaolin and carrageenan into the joint. These receptor antagonists, however, did not have an effect on the joint edema. These findings provide evidence for a potential role of peripheral NMDA and non-NMDA receptors in nociceptive transmission.

Long-term potentiation in spinothalamic neurons.

Sensitization of nociceptive dorsal horn neurons, including spinothalamic tract (STT) cells, is thought to underlie the development of secondary hyperalgesia and allodynia following tissue injury. In central sensitization, responses to stimulation of sensory receptors are enhanced without any change in the excitability of the primary afferent neurons. We hypothesize that central sensitization of STT neurons is a variety of long-term potentiation (LTP). Evidence that LTP occurs in the spinal cord is reviewed. Neurotransmitters that trigger central sensitization include excitatory amino acids and peptides. Evidence for this is that co-activation of N-methyl-D-aspartate and NK1 receptors can produce long-lasting increases in the responses of STT cells, and antagonists of these receptors prevent central sensitization. Responses to excitatory amino acids increase and those to inhibitory amino acids decrease during central sensitization, presumably accounting for the changed excitability of STT cells. We believe these changes result from the activation of signal transduction pathways, including the protein kinase C, NO/protein kinase G and protein kinase A cascades. Recent evidence shows that calcium/calmodulin dependent kinase II (CaMKII) is also upregulated early in the process of central sensitization and that several types of ionotropic glutamate receptors become phosphorylated. It is proposed that the phosphorylation of neurotransmitter receptors leads to alterations in the sensitivity of these receptors and to central sensitization. Comparable events occur during LTP in brain structures.

Is there a pathway in the posterior funiculus that signals visceral pain

&NA; The present report provides evidence that axons in the medial part of the posterior column at T10 convey ascending nociceptive signals from pelvic visceral organs. This evidence was obtained from human surgical case studies and histological verification of the lesion in one of these cases, along with neuroanatomical and neurophysiological findings in animal experiments. A restricted lesion in this area can virtually eliminate pelvic pain due to cancer. The results remain excellent even in cases in which somatic structures of the pelvic body wall are involved. Following this procedure, neurological testing reveals no additional neurological deficit. There is no analgesia to pinprick stimuli applied to the body surface, despite the relief of the visceral pain. Since it is reasonable to attribute the favorable results of limited midline myelotomies to the interruption of axons of visceral nociceptive projection neurons in the posterior column, we have performed experiments in rats to test this hypothesis. The results in rats indicate that the dorsal column does indeed include a nociceptive component that signals pelvic visceral pain. The pathway includes neurons of the postsynaptic dorsal column pathway at the L6‐S1 segmental level, axons of these neurons in the fasciculus gracilis, and neurons of the nucleus gracilis and the ventral posterolateral nucleus of the thalamus.

Factors influencing peripheral nerve stimulation produced inhibition of primate spinothalamic tract cells

&NA; Several factors that influence the inhibition of primate spinothalamic tract (STT) cells produced by repetitive peripheral conditioning stimulation have been studied. Identified STT cells were recorded from the lumbosacral spinal cord in intact, anesthetized monkeys. In addition, presumed STT cells were recorded from unanesthetized, decerebrate or decerebrate, spinalized monkeys; these cells were identified by antidromic activation from the contralateral ventral lateral funiculus of the upper cervical spinal cord. Activity of the STT cells was evoked by electrically stimulating the sural nerve with pulses having an intensity strong enough to activate C fibers. The C fiber evoked STT cell activity was compared before, during and after repetitive conditioning stimuli applied to the tibial nerve for 5 min. By applying graded strengths of conditioning stimuli, it was found that the A&dgr; fiber group is the most important for producing inhibition of STT cells, although significant additional effects were also produced by the A&agr;&bgr; and C fiber groups. Conditioning stimuli with fixed intensity at different frequencies showed that the higher the frequency the more powerful the inhibition within the range we tested (0.5–20 Hz). The inhibition produced by peripheral nerve stimulation was segmentally organized, so the most effective nerve in producing inhibition amongst those tested was the ipsilateral tibial nerve. The contralateral sciatic nerve, the ipsilateral median nerve and the contralateral median nerve were less effective in that order. The results of the present experiments suggest that the most effective way to produce analgesia by peripheral nerve stimulation would be by high frequency stimulation of a nerve innervating the area from which pain originates with an intensity at least strong enough to activate A&dgr; fibers.

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

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

Neural changes in acute arthritis in monkeys. I. Parallel enhancement of responses of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids

Somatosensory neurons of the spinal cord, including projection neurons, become hyperexcitable to mechanical stimuli during the development of experimental arthritis in rats and cats and hence are suggested to participate in the generation of arthritic hyperalgesia in humans. The experiments described here show a potentiation of the responses of spinothalamic tract (STT) neurons in monkeys during the development of an acute arthritis. The results demonstrate that the responses of STT neurons to mechanical stimuli and to iontophoretically applied excitatory amino acids (EAAs), particularly those acting at non-N-methyl-D-aspartate (non-NMDA) receptors, become enhanced during the development of inflammation produced by intra-articular injection of kaolin and carrageenan. Since the enhancement of both responses follows a similar time course, the results of this work suggest a role for EAAs in the hyperalgesia associated with arthritis and hence may provide a possible pharmacologic target for alleviation and/or prevention of arthritic pain.