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 wildtype 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 monocytes͞macrophages 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.T he chemotactic cytokine or chemokine receptor family is the largest family of G protein-coupled receptors. Accordingly, the number of chemokines that binds to these receptors is large, with Ͼ50 chemokine peptides having been identified to date (for review, see ref. 1). Chemokine biology is further complicated by individual chemokines interacting with more than one receptor and chemokine receptors potentially binding more than one chemokine. Predominantly, chemokine receptors are expressed by leukocytes, and the specific interactions of chemokines with their cognate receptors are major determinants of the trafficking and localization of leukocyte subsets within tissue compartments. A subset of chemokines exhibit potent chemoattractant activity for monocytes; one of them, monocyte chemoattractant protein 1 (MCP-1), stimulates monocyte transendothelial migration (extravasation) and preferentially binds to the chemotactic cytokine receptor (CCR), CCR2. Mice lacking either MCP-1 or CCR2 show a marked attenuation of monocyte recruitment in response to various inflammatory stimuli, as well as a reduction in the development of inflammatory lesions in models of CNS demyelinating disease (2, 3). Moreover, in CCR2-deficient mice, macrophage recruitment to sites of neuronal damage is reduced, with a consequent decrease in demyelination (4, 5).Although inflammatory ...
The transmission of pain signals after injury or inflammation depends in part on increased excitability of primary sensory neurons. Nociceptive neurons express multiple subtypes of voltagegated sodium channels (Na V1s), each of which possesses unique features that may influence primary afferent excitability. Here, we examined the contribution of Na V1.9 to nociceptive signaling by studying the electrophysiological and behavioral phenotypes of mice with a disruption of the SCN11A gene, which encodes Na V 1.9. Our results confirm that Na V1.9 underlies the persistent tetrodotoxin-resistant current in small-diameter dorsal root ganglion neurons but suggest that this current contributes little to mechanical thermal responsiveness in the absence of injury or to mechanical hypersensitivity after nerve injury or inflammation. However, the expression of Na V1.9 contributes to the persistent thermal hypersensitivity and spontaneous pain behavior after peripheral inflammation. These results suggest that inflammatory mediators modify the function of NaV1.9 to maintain inflammation-induced hyperalgesia.T he generation and propagation of action potentials in sensory neurons depends on the activity of voltage-gated sodium channels (Na V 1s). The differential expression of Na V 1 subtypes in distinct classes of sensory neurons, combined with their unique biophysical properties, suggest specific roles for each subtype in sensory transmission. Sodium channels in sensory neurons can be classified pharmacologically as sensitive to block by low nanomolar concentrations of tetrodotoxin (TTX) or resistant to Ͼ1 M TTX (1, 2).The contribution of TTX-resistant Na V 1 channel subtypes to the transmission of pain signals is an important area of focus: TTXresistant current carries the majority of charge during action potentials in nociceptive neurons (3), and this current is dynamically regulated in response to injury (4, 5). Na V 1.8, expressed primarily in C-fibers (6), underlies a TTX-resistant current with a high threshold for activation and steady-state inactivation and slow kinetics (7). Comparisons between dorsal root ganglion (DRG) neurons from WT and Na V 1.8 null mutant (Ϫ͞Ϫ) mice suggest that Na V 1.8 contributes the majority of the inward current flowing during action potentials in small-diameter neurons (8). Antisense oligonucleotides directed against Na V 1.8 implicate this channel in both neuropathic (9) and inflammatory (10) pain conditions in rats, although Na V 1.8Ϫ͞Ϫ mice displayed only a mild phenotype (7,11).The functional role of Na V 1.9, another subtype selectively expressed in nociceptors (12), remains poorly defined. The primary sequence of Na V 1.9 predicts that this subtype conducts sodium currents resistant to TTX (13). Indeed, a second TTX-resistant current is present in DRG neurons from Na V 1.8 knockout mice (14). This current has been referred to as the persistent, TTXresistant current because of its negative threshold for activation and depolarized midpoint of inactivation, resulting in a significant windo...
We have identified four new mu-opiod receptor (MOR)-1 exons, indicating that the gene now contains at least nine exons spanning more than 200 kilobases. Replacement of exon 4 by combinations of the new exons yields three new receptors. When expressed in Chinese hamster ovary cells, all three variants displayed high affinity for mu-opioid ligands, but kappa and delta drugs were inactive. However, there were subtle, but significant, differences in the binding profiles of the three variants among themselves and from MOR-1. Immunohistochemically, the major variant, MOR-1C, displayed a regional distribution quite distinct from that of MOR-1. Region-specific processing also was seen at the mRNA level. Antisense mapping revealed that the four new exons were all involved in morphine analgesia. Together with two other variants generated from alternative splicing of exon 4, there are now six distinct MOR-1 receptors.
Although the neurokinin-1 (NK-1)/substance P (SP) receptor is expressed by neurons throughout the spinal dorsal horn, noxious chemical stimulation in the normal rat only induces internalization of the receptor in cell bodies and dendrites of lamina I. Here we compared the effects of mechanical and thermal stimulation in normal rats and in rats with persistent hindpaw inflammation. Electron microscopic analysis confirmed the upregulation of receptor that occurs with inflammation and demonstrated that in the absence of superimposed stimulation, the increased receptor was, as in normal rats, concentrated on the plasma membrane. In general, noxious mechanical was more effective than noxious thermal stimulation in inducing NK-1 receptor internalization, and this was increased in the setting of inflammation. Although a 5 sec noxious mechanical stimulus only induced internalization in 22% of lamina I neurons in normal rats, after inflammation, it evoked near-maximal (98%) internalization in lamina I, produced significant changes in laminae III-VI, and expanded the rostrocaudal distribution of neurons with internalized receptor. Even non-noxious (brush) stimulation of the inflamed hindpaw induced internalization in large numbers of superficial and deep neurons. For thermal stimulation, the percentage of cells with internalized receptor increased linearly at Ͼ45°C, but in normal rats, these were restricted to lamina I. After inflammation, however, the 52°C stimulus also induced internalization in 25% of laminae III-IV cells. These studies provide a new perspective on the reorganization of dorsal horn circuits in the setting of persistent injury and demonstrate a critical contribution of SP.
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