William J. Roberts

A hypothesis on the physiological basis for causalgia and related pains.

&NA; A hypothesis is presented concerning the neuronal mechanisms which subserve the sympathetically maintained pains such as causalgia and reflex sympathetic dystrophy. The hypothesis rests on two assumptions: (1) that a high rate of firing in spinal wide‐dynamic‐range (WDR) or multireceptive neurons results in painful sensations; and (2) that nociceptor responses associated with trauma can produce long‐term sensitization of WDR neurons. The hypothesis states that chronic sympathetically maintained pains are mediated by activity in low‐threshold, myelinated mechanoreceptors, that this afferent activity results from sympathetic efferent actions upon the receptors or upon afferent fibers ending in a neuroma and that these afferent fibers evoke sufficient activity in sensitized spinal WDR neurons to produce a painful sensation. This hypothesis is based on known characteristics of these neuronal populations studied in experimental animals and on the observed sensory disturbances reported in patients successfully treated with sympathetic blocks. This hypothesis does not require nerve injury or dystrophic tissue. It explains both the continuous pain and the allodynia that are common to these syndromes and their abolition by sympathetic block. Specific changes are proposed in the diagnosis and treatment of post‐traumatic pains.

Climbing fiber responses of cerebellar Purkinje cells to passive movement of the cat forepaw

The activity of cerebellar Purkinje cells during controlled and passive movement of the forepaw was studied in the cat. Burst responses characteristic of activation by climbing fibers were observed in Purkinje cells in lobules Vb and Vc of the cerebellar vermis and paravermis. The climbing fiber responses followed the onset of a movement with a latency ranging from 20 to 60 msec depending upon movement type and amplitude. Responsive Purkinje cells were localized in a well defined parasagittal strip very near the paravermal vein in lobules Vb and Vc. Cells within the responsive strip responded with identical response probabilities and latencies for any particular type of movement presentation. Responses were independent of starting paw position and direction of movement. Climbing fiber responses could be evoked by extremely small movements with most cells responding to displacements of 50 mum. The latencies and probabilities for climbing fiber responses were inversely related to movement amplitude with latencies as long as 80 msec for very small displacements.

Characterization of spinal somatosensory neurons having receptive fields in lumbar tissues of cats

&NA; In pentobarbital anesthetized cats, extracellular unitary recordings were made from neurons in the extreme lateral dorsal horn of spinal segments L4–5. All 118 units reported had receptive fields in deep somatic tissues and/or skin of the lumbar region, hip and/or proximal leg. Neurons were functionally characterized according to their responses to non‐noxious and noxious mechanical stimuli and to injections of algogens. Most neurons (92%) were either wide‐dynamic range (WDR) or nociceptive specific (NS), and most of these had very large nociceptive receptive fields in the back/hip/leg that included both skin and deep somatic tissues innervated through both the dorsal (back/hip) and ventral (leg/ventral spine) rami. Most (72%) were ‘hyperconvergent’ in that they were responsive to stimulation of many different somatic tissues including skin, muscles, facet joint capsules, ligaments, and periosteum. Some units were tested and found also to be activated by noxious stimulation of spinal dura and ventral annulus fibrosis and ventral longitudinal ligament. Twelve of 22 neurons tested were found to have ascending axons extending beyond Th10. The nocireceptive neurons (NS and WDR) in the population tested are suitable for processing information about tissue damage in deep somatic tissues in the back, hip and proximal leg. The apparent relative paucity of such neurons and their very large hyperconvergent receptive fields suggest that sensations served by these neurons, such as low back and referred leg pain, would be neither well localized nor attributable to pathology in a specific tissue. These deductions, based on physiological characteristics in cats, are consistent with clinical reports from humans who experience pain as a consequence of spinal or paraspinal injuries.

I. Spinal recordings suggest that wide-dynamic-range neurons mediate sympathetically maintained pain

&NA; In order to determine which classes of spinal neurons are capable of mediating sympathetically maintained pain, recordings were made from single somatosensory neurons in spinal cords of anesthetized cats. Each neuron was functionally identified with mechanical stimuli, and its responses to electrical stimulation of the sympathetic trunk were recorded. Nearly half (45%) of the wide‐dynamic‐range (WDR) neurons tested were activated by sympathetic stimulation, but none of the high threshold (nociceptor‐specific) neurons and only 17% of the low threshold neurons were activated. Sympathetic activation was most common for WDR neurons that had the following: receptive fields proximal to the toes, low thresholds for mechanical activation, and both rapidly and slowly adapting responses to pressure. The predominant WDR response to sympathetic stimulation was long latency (>1 sec) excitation. Sympathetic activation of WDR neurons was abolished by each of the following procedures: subcutaneous injection of local anesthetic, cooling of the receptive field with ice, and intravenous injection of the alpha‐adrenergic blocker, phentolamine. The axons of some sympathetically activated WDR were shown to project to higher centers. These results indicate that WDR neurons are the only spinal nociceptive neurons activated by sympathetic efferent activity in this preparation. Therefore, WDR neurons, rather than high threshold neurons, are most likely to mediate the spinal component of sympathetically maintained pain. These results provide supporting evidence for our previous hypothesis [30] that sympathetically maintained pain is mediated by myelinated mechanoreceptors acting on sensitized WDR neurons. Our results also demonstrate that sympathetic activation of WDR neurons is mediated by an alpha‐adrenergic mechanism in the skin.

Sympathetic activation of unmyelinated mechanoreceptors in cat skin

In single unit recordings from the saphenous nerve in anesthetized cats, afferent units were functionally identified as unmyelinated (C) mechanoreceptors. All units responded to stimulation of the sympathetic trunk with a repetitive discharge which was maintained throughout the period of stimulation. This discharge was asynchronous with respect to efferent activity and was unaffected by brief occlusion of the arterial blood supply. The mechanism underlying the strong excitatory action of the sympathetic system on these afferents is not known although changes in blood flow and temperature can be ruled out. It is suggested that the primary function of these afferents may be to signal conditions within the skin for regulatory purposes rather than to encode external mechanical events.

Slowly developing placebo responses confound tests of intravenous phentolamine to determine mechanisms underlying idiopathic chronic low back pain.

&NA; Phentolamine (30 mg) was administered intravenously to subjects with idiopathic chronic low back pain in a novel placebo‐controlled test to determine whether this &agr;‐adrenergic antagonist would reduce their pain. The effects of infusions on spontaneous pain and stimulus‐evoked pains (touch, cold, tapping and deep pressure) were evaluated separately. All subjects gave strong placebo responses (reduced pain) that prevented assessment of specific drug effects. The placebo responses had onset latencies of 15–60 min, developed slowly over the next 15–45 min and persisted for hours or several days. These results not only reinforce the understanding that placebo controls are essential in the evaluation of drugs or other palliative procedures on patients with chronic pain but also indicate that the control paradigms must allow for placebo effects that are slow to develop and very persistent.

Spinal projections of cat primary afferent fibers innervating lumbar facet joints and multifidus muscle

The spinal projections of small-caliber (presumably nociceptive) afferents arising from lumbar spinal joints and muscles were examined using anterograde transport of WGA-HRP. Injections of WGA-HRP into these structures gave rise to similar, rostro-caudally extensive patterns of spinal labeling indicating that many afferents innervating one facet joint or paraspinal muscle terminate bilaterally in laminae I-II, V-VIII, and X of the lumbar, sacral, and thoracic spinal cord. These diffuse patterns of terminal arborization are reminiscent of visceral input and contrast with the more restricted unilateral terminal fields reported for afferents innervating more distal hindlimb tissues.

II. Identification of afferents contributing to sympathetically evoked activity in wide-dynamic-range neurons

&NA; The purpose of this study was to determine which types of mechanoreceptor afferents contribute to sympathetically evoked activity in wide‐dynamic‐range (WDR) neurons — the spinal neurons thought to mediate sympathetically maintained pain. The experimental approach was to record and compare activity evoked in single WDR neurons, hair afferents, and slowly adapting type I (SAI) afferents in anesthetized cats. During electrical stimulation of the sympathetic trunk, WDR neurons responded with either an early transient burst of activity, sustained activity, or both. The early transient response was observed only in neurons with piloerection in the receptive field; this response had a similar time course to sympathetically evoked activity in hair afferents with piloerection in the receptive field. The sustained response that occurred in some WDR neurons was independent of piloerection and was similar in time course to the response evoked in SAI afferents by sympathetic stimulation. We conclude that hair and SAI afferents contribute to different components of sympathetically evoked activity in WDR neurons and that both types of afferents are likely to be involved in sympathetically maintained pain in humans.

Post-sympathectomy neuralgia: hypotheses on peripheral and central neuronal mechanisms

Post-sympathectomy neuralgia is proposed here to be a complex neuropathic and central deafferentation/reafferentation syndrome dependent on: (a) the transection, during sympathectomy, of paraspinal somatic and visceral afferent axons within the sympathetic trunk; (b) the subsequent cell death of many of the axotomized afferent neurons, resulting in central deafferentation; and (c) the persistent sensitization of spinal nociceptive neurons by painful conditions present prior to sympathectomy. Viscerosomatic convergence, collateral sprouting of afferents, and mechanisms associated with sympathetically maintained pain are all proposed to be important to the development of the syndrome.

Sympathetic nervous system influence on acute and chronic pain

Publisher Summary This chapter discusses mechanisms by which sympathetic efferent fibers can affect activity in both nociceptive and non-nociceptive sensory afferents. Sympathetic activation of non-nociceptive mechanoreceptors results in pain because the elicited afferent activity intensely activates certain pain-related spinal neurons—wide-dynamic-range neurons made hyperexcitable by previous nociceptive input; while sympathetically induced release of prostaglandins involves nociceptive rather than non-nociceptive afferents. Sympathetically induced pathologic conditions may also contribute to pain in certain disorders. The chapter also discusses inter-related topics of reflex sympathetic dystrophy syndrome (RSDS), sensitization of spinal neurons, and sympathetic activation of low-threshold mechanoreceptors. Evidence cited in the chapter suggests that post-sympathectomy pain depends upon development of hyperactivity in spinal neurons—a hyperactivity because of transection, during sympathectomy, of visceral afferents projecting through sympathetic trunk.