Patrick M. Dougherty

Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms

Cancers and cancer treatments produce multiple symptoms that collectively cause a symptom burden for patients. These symptoms include pain, wasting, fatigue, cognitive impairment, anxiety, and depression, many of which co‐occur. There is growing recognition that at least some of these symptoms may share common biologic mechanisms.

Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury.

The change in staining density of glial fibrillary acidic protein (GFAP) was analyzed in rats that sustained a chronic constriction injury produced by sutures tied loosely around one sciatic nerve. This injury model of peripheral neuropathy resulted in a behavioral hyperalgesia evidenced by a decrease in mean foot withdrawal latency to radiant heat. Increased GFAP immunostaining was observed in the gray matter of the spinal cord ipsilateral to the lesion and specific to spinal segments in which the sciatic nerve is distributed. Elevated GFAP staining density was attributed primarily to hypertrophy of astrocytes rather than their proliferation or migration since counts of astrocyte profiles demonstrated no significant difference when comparing the lesioned to the control side. The magnitude of the increase in GFAP staining correlated with the degree of hyperalgesia. Thus, these data suggest that astrocytes participate in the sequelae occurring in the dorsal horn following constriction injury of a peripheral nerve.

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.

Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients

&NA; Taxol produces neuropathic pain with three distinct zones of involvement in the extremities. Most distally is an area of on‐going pain and proximal to this is a zone of sensory disturbance but not overt pain. These two areas were confined in all but one case to the glabrous skin of the hands and/or feet. More proximal is an area not recognized by the patients as involved with pain or sensory disturbance yet wherein quantitative sensory tests nevertheless reveal altered sensibility. Impairment of perception to light touch, normally conveyed by myelinated fibers, was dramatically altered in all three areas, being approximately 50‐fold greater than normal in areas of pain and sensory disturbance as well as in areas of skin perceived by the patients as not affected. Impairment of perception to sharpness, normally conveyed by small myelinated fibers, was most pronounced in areas of on‐going pain, intermediate in areas of sensory disturbance and near baseline in more proximal skin of chemotherapy patients. In contrast to mechanical sensibility, thermal thresholds for warm and heat pain detection were normal throughout. Finally, chemotherapy patients showed paradoxical burning pain to skin cooling that was most pronounced in proximal areas of skin thought to be unaffected by the patients, intermediate in the border zone of altered sensibility and least pronounced in areas of on‐going pain. These data suggest that taxol produces a neuropathy characterized by pronounced impairment of function in A‐beta myelinated fibers, intermediate impairment of A‐delta myelinated fibers, and a relative sparing of C‐fibers.

A cytokine-based neuroimmunologic mechanism of cancer-related symptoms.

While many of the multiple symptoms that cancer patients have are due to the disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive dysfunction and affective symptoms are treatment related, and may lead to treatment delays or premature treatment termination. This symptom burden, a subjective counterpart of tumor burden, causes significant distress. Progress in understanding the mechanisms that underlie these symptoms may lead to new therapies for symptom control. Recently, some of these symptoms have been related to the actions of certain cytokines that produce a constellation of symptoms and behavioral signs when given exogenously to both humans and animals. The cytokine-induced sickness behavior that occurs in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines has much in common with the symptoms experienced by cancer patients. Accordingly, we propose that cancer-related symptom clusters share common cytokine-based neuroimmunologic mechanisms. In this review, we provide evidence from clinical and animal studies that correlate the altered cytokine profile with cancer-related symptoms. We also propose that the expression of coexisting symptoms is linked to the deregulated activity of nuclear factor-kappa B, the transcription factor responsible for the production of cytokines and mediators of the inflammatory responses due to cancer and/or cancer treatment. These concepts open exciting new avenues for translational research in the pathophysiology and treatment of cancer-related symptoms.

Pallidal activity during dystonia: somatosensory reorganisation and changes with severity.

A woman with progressive, medically intractable right upper limb dystonia underwent a pallidotomy with only transient improvement. During the procedure her dystonia became more severe as she repeatedly made a fist to command in order to provoke dystonia transiently (movement provoked dystonia). Comparisons within cells in the internal segment of the globus pallidus (Gpi) disclosed that the firing rate was the same at rest, with making a fist, and during movement provoked dystonia. However, the firing rate compared between cells decreased significantly throughout the procedure as the patient made a fist repeatedly. During the second half of the procedure the firing rate of cells in the Gpi was similar to that in hemiballismus. The proportion of cells in the GPi which responded to sensory stimulation was significantly higher in dystonia (53%) than in hemiballismus (13%). These results suggest that pallidal activity can correlate inversely with the severity of dystonia, perhaps due to activity dependent changes in neuronal function resulting from repeated voluntary movement.

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.

Neural changes in acute arthritis in monkeys. IV : Time-course of amino acid release into the lumbar dorsal horn

Extracellular levels of amino acids were measured during the development of experimental arthritis in anesthetized monkeys. Levels of glutamate, aspartate, glycine, serine, glutamine, taurine, cysteic acid and asparagine were each measured in consecutive 30 min samples before, during and for several hours after injection of kaolin and carrageenan into the articular capsule of one knee. Samples were obtained via a microdialysis probe placed in the lumbar dorsal horn ipsilateral to the injected knee and assayed using HPLC with fluorescence detection. Glutamate, aspartate, glycine and serine increased transiently following intra-articular injection of inflammatory agents. During this period glutamine levels decreased. A second phase of release then occurred which included more prolonged changes in amino acid levels that were sometimes of greater magnitude than those immediately following the injection. In animals which were later observed to have depletion of SP in the dorsal horn of the inflamed side, taurine levels increased starting after the Glu, Asp and Gly had plateaued at near baseline concentrations. Thus during the first stages of joint inflammation EAAs are released into the dorsal horn, followed by increased levels of IAAs, possibly representing activation of the descending endogenous analgesia system. This phase is followed by a semiacute response consisting in part of increased extracellular levels of SP and Tau. While SP is presumably part of an ascending nociceptive transmission system, Tau could be part of a second system aimed at reducing excessive neural activity including neural transmission resulting in intense maintained pain.

Combined application of excitatory amino acids and substance P produces long-lasting changes in responses of primate spinothalamic tract neurons

Sensitization of dorsal horn neurons following injury may underlie the generation of secondary hyperalgesia and so the chemical basis of sensitization is now receiving considerable attention. The present study used microiontophoretic applications of excitatory amino acids (EAAs) and substance P (SP) to test their roles in the sensitization of primate spinothalamic tract (STT) neurons. Of 70 STT cells examined in laminae I-VI of the dorsal horn, 40 showed an increase in responses to one or more EAAs following their co-application with SP. The increased responses were usually specific to either N-methyl-D-aspartate (NMDA) or to the non-NMDA agonists, quisqualate (QUIS) or D,L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA). The enhancement of EAA responses was long-lasting (> 15 min) in 18 cases, was accompanied by similarly long-lasting increases in responses to mechanical stimulation of the receptive field in 14 cases and was accompanied by an increase in responses to either glutamate (Glu) or aspartate (Asp) in eleven cases. A global decrease in all EAA responses tested was produced in 26 other STT neurons. The inhibition, unlike the increases, was generalized to both NMDA and non-NMDA ligands, was long-lasting in only six cases and was never accompanied by a change in the responses to mechanical stimuli. The excitatory and inhibitory effects of SP on the responses to NMDA were uniformly reversed by the NK-1 receptor selective antagonist, CP96345. In contrast, only the inhibitory effects of SP on the responses to QUIS or AMPA were reversed by CP96345. The long-lasting enhancement of EAA responses by SP may follow the combined synaptic release of the natural ligands in vivo, resulting in the sensitization of dorsal horn neurons and secondary hyperalgesia. However, the reductions in EAA responses produced by SP are problematic for this hypothesis and need further elucidation.

Is large myelinated fiber loss associated with hyperalgesia in a model of experimental peripheral neuropathy in the rat

&NA; Recently it has been shown that placement of 4 loose chromic gut sutures around the rat sciatic nerve produces hyperalgesia. A possible mechanism underlying this hyperalgesia is a preferential loss of large myelinated fibers. A difficulty, however, is that neuropathic symptoms are not static and the time course of the axon loss has not been determined. To remedy this deficit, the present study relates axonal changes to the behavior of the animal at various times after induction of the neuropathy. The findings are that a loss of all axon types, with a preferential loss of large myelinated axons, is associated with the development of heat hyperalgesia. As the axon loss progresses, however, the hyperalgesia lessens. In addition, at 28 days post surgery there are essentially no large myelinated axons in the distal segment, but the signs of hyperalgesia have almost resolved. These findings indicate that the onset of the hyperalgesia is accompanied by a preferential loss of large fibers and by a lesser but still substantial loss of small myelinated and unmyelinated axons. The subsequent course of the hyperalgesia, however, is not in any obvious way related to the proportions of large myelinated fibers in the affected nerve.