Neuropathic Pain Responses Research Articles

Feeling No (Chronic) Pain

Abbadie et al. investigated the role of chemotactic chemokine receptor 2 (CCR2) in pain and discovered evidence implicating this receptor in chronic neuropathic pain. Chronic neuropathic pain, a condition that can have substantial effects on quality of life and may interfere with common activities of daily living, can be difficult to treat and remains poorly understood. Abbadie et al. compared the responses of wild-type mice and mutant mice lacking CCR2, which mediates the chemotactic response of monocytes to the inflammatory chemokine monocyte attractant protein-1 (MCP-1), in several models of pain. After injury to the sciatic nerve, the mutant mice lacked a behavioral response associated with chronic neuropathic pain. In wild-type mice, nerve injury led to increased levels of CCR2 in the sciatic nerve and dorsal root ganglia. In addition, numerous CCR2-immunoreactive macrophages were identified in the sciatic nerve and CCR2-immunoreactive microglia were observed in the spinal cord. The CCR2 knockout mice had fewer astrocytes in the dorsal horn of the spinal cord after nerve injury than did wild-type mice, and their microglia showed lower levels of p38 mitogen-activated protein kinase. Both of these observations are indicative of reduced glial activation. CCR2's role in chronic neuropathic pain could lead to new therapies for this condition.C. Abbadie, J. A. Lindia, A. M. Cumiskey, L. B. Peterson, J. S. Mudgett, E. K. Bayne, J. A. DeMartino, D. E. MacIntyre, M. J. Forrest, Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. U.S.A. 100, 7947-7952 (2003).[Abstract][Full Text]

Feeling No (Chronic) Pain

Abbadie et al. investigated the role of chemotactic chemokine receptor 2 (CCR2) in pain and discovered evidence implicating this receptor in chronic neuropathic pain. Chronic neuropathic pain, a condition that can have substantial effects on quality of life and may interfere with common activities of daily living, can be difficult to treat and remains poorly understood. Abbadie et al. compared the responses of wild-type mice and mutant mice lacking CCR2, which mediates the chemotactic response of monocytes to the inflammatory chemokine monocyte attractant protein-1 (MCP-1), in several models of pain. After injury to the sciatic nerve, the mutant mice lacked a behavioral response associated with chronic neuropathic pain. In wild-type mice, nerve injury led to increased levels of CCR2 in the sciatic nerve and dorsal root ganglia. In addition, numerous CCR2-immunoreactive macrophages were identified in the sciatic nerve and CCR2-immunoreactive microglia were observed in the spinal cord. The CCR2 knockout mice had fewer astrocytes in the dorsal horn of the spinal cord after nerve injury than did wild-type mice, and their microglia showed lower levels of p38 mitogen-activated protein kinase. Both of these observations are indicative of reduced glial activation. CCR2's role in chronic neuropathic pain could lead to new therapies for this condition. C. Abbadie, J. A. Lindia, A. M. Cumiskey, L. B. Peterson, J. S. Mudgett, E. K. Bayne, J. A. DeMartino, D. E. MacIntyre, M. J. Forrest, Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. U.S.A. 100 , 7947-7952 (2003). [Abstract] [Full Text]

Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2.

Mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2) have a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions in models of demyelinating disease. In the present study, we compared nociceptive responses in inflammatory and neuropathic models of pain in CCR2 knockout and wild-type mice. In acute pain tests, responses were equivalent in CCR2 knockout and wild-type mice. In models of inflammatory pain, CCR2 knockout mice showed a 70% reduction in phase 2 of the intraplantar formalin-evoked pain response but only a modest (20-30%) and nonsignificant reduction of mechanical allodynia after intraplantar Freund's adjuvant (CFA). In a model of neuropathic pain, the development of mechanical allodynia was totally abrogated in CCR2 knockout mice. CFA administration induced marked up-regulation of CCR2 mRNA in the skin and a moderate increase in the sciatic nerve and dorsal root ganglia (DRG). In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Disruption of Schwann cells in response to nerve lesion resulted in infiltration of CCR2-positive monocytes/macrophages not only to the neuroma but also to the DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. Collectively, these data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.

CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?

Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB(2) (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.

A Role of the Ubiquitin–Proteasome System in Neuropathic Pain

Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.

Intrathecal lithium reduces neuropathic pain responses in a rat model of peripheral neuropathy

We tested the ability of lithium (Li +) to block heat hyperalgesia, cold allodynia, mechanical allodynia and mechanical hyperalgesia in rats experimentally subjected to painful peripheral neuropathy. Chronic constrictive injury (CCI) to the sciatic nerve induced persistent hyperalgesia and allodynia. Intrathecal injection of Li + (2.5–40 μmol) into the region of lumbar enlargement dose-dependently reduced heat hyperalgesia, cold allodynia and mechanical allodynia for 2–6 h after injection, but had no effect on mechanical hyperalgesia. Li + had no significant effect on responses from control and sham-operated animals. Intrathecal injection of myo-inositol (2.5 mg) significantly reversed both the anti-hyperalgesic and anti-allodynic effect of Li +. These findings suggest that intrathecal Li + suppresses neuropathic pain response in CCI rats through the intracellular phosphatidylinositol (PI) second messenger system in spinal cord neurons. Lithium (Li +) has already found widespread clinical application; these results suggest that its therapeutic utility may be extended to include treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

The Safety and Efficacy of a Single Dose (500 mg or 1 g) of Intravenous Magnesium Sulfate in Neuropathic Pain Poorly Responsive to Strong Opioid Analgesics in Patients with Cancer

Neuropathic pain may respond poorly to morphine and is often difficult to relieve. Recent attention has been drawn to the role of the N-methyl- d-aspartate (NMDA) receptor in the potentiation of neuropathic pain. Magnesium is known to block the NMDA receptor. It reduces the neuropathic pain response in animals, and attenuates postoperative pain and migraine in humans. We have examined the safety, tolerability, and efficacy of two intravenous doses of magnesium sulfate in 12 patients with neuropathic pain due to malignant infiltration of the brachial or lumbosacral plexus. The first six patients received 500 mg, the remainder 1 g. Apart from a mild feeling of warmth at the time of the injection, both doses were well tolerated. After receiving 500 mg, three patients experienced complete pain relief and two experienced partial pain relief for up to 4 hours duration; pain was unchanged in one patient. After receiving 1 g, one patient experienced complete relief and four experienced partial pain relief of similar duration; pain was unchanged in one patient. Intravenous magnesium sulfate in these doses appears to be safe and well tolerated. A useful analgesic effect may be obtained in some patients and further evaluation is warranted.

Experimental pain models and clinical chronic pain: Is plasticity enough to link them?

The central hyperexcitability observed in animal models supports a pathophysiological explanation for chronic human pain. Novel information on cholecystokinin (CCK) upregulation offers a rationale for reduced opioid response in neuropathic pain. However, the basic information provided by scientists should not lead clinicians to equate experimental models to chronic human conditions. Clinicians should provide careful reports and attempt to classify pathophysiologically clinical conditions that have so far been grouped generically. [blumberg et al.; coderre & katz; dickenson; wiesenfeld-hallin et al.]

Streptozotocin-Induced Diabetes Is Associated With Altered Expression of Peptide-Encoding mRNAs in Rat Sensory Neurons

Major complications arising from diabetes mellitus include neuropathic pain and altered peripheral inflammatory responses. Somatostatin (SOM), calcitonin gene-related peptide (CGRP), and substance P (SP) are neuropeptides that modulate pain responses transmitted by primary sensory afferents, the cell bodies of which are located in the dorsal root ganglion (DRG). Thus, the goal of the present study was to determine whether the diabetic condition is associated with altered neuropeptide gene expression in lumbar DRG of the rat. We employed an established animal model in which streptozotocin (STZ, 55 mg/kg) is administered to 6-week-old rats. The hallmark symptoms of hyperglycemia (blood glucose > 400 mg/dl), polydipsia, polyuria, and severe weight loss were maximal at 6 weeks postadministration, at which time animals were sacrificed. For determination of peptide-encoding mRNAs distributed in DRG neurons, in situ hybridization histochemistry utilizing 35 S-end-labeled oligonucleotides complimentary to sequences of preprosomatostatin (PPSOM), preprocalcitonin gene related peptide (PPCGRP), preprotachykinin (PPT), or preproneuropeptide Y (PPNPY) mRNA was performed. Silver grains were detected overlying DRG cells by autoradiography on sections of tissue counterstained with thionin. Semiquantitative analysis of differences in silver grain signal were made using an image analysis system, which expressed signals as fCi/μm 2 . In diabetic rats there was a significant decrease in DRG PPSOM (54%, p < 0.01), and PPCGRP (33%, p < 0.05) mRNA hybridization from the normal values. PPT mRNA hybridization signal and SP-like immunoreactivity were not significantly changed in diabetic rat DRGs compared to control. In contrast, there was an increase in the number of cells labeled with PPNPY hybridization in DRG from diabetic rats. These data suggest that CGRP and SOM synthesis in primary sensory neurons is reduced in STZ-induced diabetic rats. These changes could contribute to the painful neuropathies and altered inflammatory responses seen in diabetes mellitus.

Streptozotocin-induced diabetes is associated with altered expression of peptide-encoding mRNAs in rat sensory neurons.

Major complications arising from diabetes mellitus include neuropathic pain and altered peripheral inflammatory responses. Somatostatin (SOM), calcitenin gene-related peptide (CGRP), and substance P (SP) are neuropeptides that modulate pain responses transmitted by primary sensory afferents, the cell bodies of which are located in the dorsal root ganglion (DRG). Thus, the goal of the present study was to determine whether the diabetic condition is associated with altered neuropeptide gene expression in lumbar DRG of the rat. We employed an established animal model in which streptozotocin (STZ, 55 mg/kg) is administered to 6 week-old rats. The hallmark symptoms of hyperglycemia (blood glucose > 400 mg/dl), polydipsia, polyuria, and severe weight loss were maximal at 6 weeks postadministration, at which time animals were sacrificed. For determination of peptide encoding mRNAs distributed in DRG neurons, in situ hybridization histochemistry utilizing S-end-labeled oligonucleotides complimentary to sequences of preprosomatostatin (PPSOM), preprocalcitonin gene related peptide (PPCGRP), preprotachykinin (PPT), or preproneuropeptide Y (PPNPY) mRNA was performed. Silver grains were detected overlying DRG cells by autoradiography on sections of tissue counterstained with thionin. Semiquantitative analysis of differences in silver grain signal were made using an image analysis system, which expressed signals as fCi/microns2. In diabetic rats there was a significant decrease in DRG PPSOM (54%, p < 0.01), and PPCGRP (33%. p < 0.05) mRNA hybridization from the normal values PPT mRNA hybridization signal and SP-like immunoreactivity were not significantly changed in diabetic rat DRGs compared to control. In contrast, there was an increase in the number of cells labeled with PPNPY hybridization in DRG from diabetic rats. These data suggest that CGRP and SOM synthesis in primary sensory neurons is reduced in STZ-induced diabetic rats. These changes could contribute to the painful neuropathies and altered inflammatory responses seen in diabetes mellitus.