Dorsal column lesion prevents mechanical hyperalgesia and allodynia in osteotomy model

Houghton, Andrea K.; Hewitt, Elena; Westlund, Karin N.

doi:10.1016/s0304-3959(99)00034-2

Cited by 19 publications

(8 citation statements)

References 26 publications

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“…The known projections of these fibers to the brainstem, along with the observations of plasticity at levels as far rostral as the midbrain after injury to peripheral nerves (Kovelowski et al, 2000), point to a role of supraspinal sites in the nerve injury-induced pain state. This concept is supported by various lesion studies of ascending pathways (Houghton et al, 1999;Sun et al, 2001) as well as by the emergence of evidence of the critical importance of descending pain facilitation pathways in nerve injury-induced pain. Specifically, blockade of nerve injuryinduced pain is seen after RVM microinjection of lidocaine (Pertovaara et al, 1996;Kovelowski et al, 2000) as well as by lesions of the DLF .…”

Section: Discussionmentioning

confidence: 89%

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

et al. 2001

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Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing -opioid receptors were targeted with a single microinjection of saporin conjugated to the -opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, significantly decreased cells expressing -opioid receptor transcript. RVM dermorphin, saporin, or dermorphin-saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin-saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin-saporin against SNL-induced pain was blocked by ␤-funaltrexamine, a selective -opioid receptor antagonist, indicating specific interaction of dermorphin-saporin with the -opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.

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Section: Discussionmentioning

confidence: 89%

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

et al. 2001

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“…Another interesting finding of the present study is that ERK is activated in the astrocytes of the dorsal column of the spinal cord, an area through which large diameter primary sensory afferents of DRG neurons project to the nucleus gracilis (48). Since this pathway has been shown to play a role in nociceptive processing (49), further investigation is certainly warranted to clearly establish the role of glia within the dorsal column in the development of tolerance to morphine‐induced analgesia.…”

Section: Discussionmentioning

confidence: 99%

Cell‐type specific activation of p38 and ERK mediates calcitonin gene‐related peptide involvement in tolerance to morphine‐induced analgesia

Wang

Chabot

et al. 2009

FASEB j.

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Tolerance to morphine-induced analgesia is a well-established phenomenon, often limiting its usefulness in the long-term treatment of pain. The mechanisms underlying tolerance are not well understood. We previously suggested a possible role for spinal calcitonin gene-related peptide (CGRP) in the development of tolerance to morphine-induced analgesia. In the present study, we demonstrate that CGRP is involved in morphine tolerance by differentially regulating the ERK-dependent up-regulation of IL-1beta, TNF-alpha, and microsomal prostaglandin E synthase-1 (mPGES-1) in astrocytes and p38-dependent up-regulation of IL-6 in microglia in the rat spinal cord. A 7-d treatment with morphine induced tolerance to the antinociceptive effect and increased phosphorylated ERK localized in astrocytes and phosphorylated p38 enriched in microglia, both effects being inhibited by blocking CGRP receptors. Interestingly, the inhibition of the ERK pathway suppressed the development of tolerance and morphine-induced up-regulation of IL-1beta, TNF-alpha, and mPGES-1. Blockade of p38 activity also inhibited the development of tolerance and morphine-induced IL-6 up-regulation. Taken together, these data suggest that chronic morphine induces the synthesis of CGRP, which in turn acts on CGRP receptors located on astrocytes and microglia to stimulate ERK and p38, respectively, leading to increased synthesis and release of proinflammatory mediators resulting in tolerance to morphine-induced analgesia.

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“…Although large myelinated fibers that project in the dorsal columns to the n. gracilis normally transmit sensations of light touch and vibration, these pathways have also been associated with pain (Angaut-Petit, 1976;Berkley and Hubscher, 1995;Willis and Westlund, 1997;Wang et al, 1999). Lesions of the dorsal columns block pelvic cancer pain (Hirshberg et al, 1996;Nauta et al, 1997), pain associated with pancreatitis, and bone pain (Houghton et al, 1997(Houghton et al, , 1999(Houghton et al, , 2001. The excitation of neurons of the n. gracilis or of the ventroposterolateral nucleus of the thalamus elicited by colorectal distension or a noxious cutaneous pinch was blocked by lesions of the dorsal columns (Al-Chaer et al, 1996a,b).…”

Section: Discussionmentioning

confidence: 99%

Selective Mediation of Nerve Injury-Induced Tactile Hypersensitivity by Neuropeptide Y

et al. 2002

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Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection into the nucleus gracilis (n. gracilis). These and other data support the possibility that tactile hyperresponsiveness after nerve injury may be selectively mediated by a low-threshold myelinated fiber pathway to the n. gracilis. Here we identify a transmitter that might selectively mediate such injury-induced tactile hypersensitivity. Neuropeptide Y (NPY), normally not detected in the dorsal root ganglion (DRG) or in the n. gracilis of rats, became markedly upregulated at both sites and in the spinal cord after spinal nerve injury. Injury-induced NPY-IR occurred predominately in large-diameter DRG cells, and the NPY-IR in the n. gracilis was blocked by dorsal rhizotomy or dorsal column lesion. NPY microinjection into the n. gracilis of uninjured rats elicited reversible tactile, but not thermal, hypersensitivity only in the ipsilateral hindpaw. Administration of anti-NPY antiserum, but not control serum or preabsorbed serum, into the n. gracilis ipsilateral to nerve injury reversed tactile, but not thermal, hypersensitivity. Similarly, microinjection of the NPY antagonists NPY(18-36) and (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate, into the n. gracilis ipsilateral to the injury reversed tactile, but not thermal, hypersensitivity. Antagonist administration into the contralateral n. gracilis had no effect on injury-induced hypersensitivity. These data suggest the selective mediation of nerve injury-induced tactile hypersensitivity by upregulated NPY via large fiber input to n. gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor antagonists would have significant implications for human neuropathic conditions.

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Dorsal column lesion prevents mechanical hyperalgesia and allodynia in osteotomy model

Cited by 19 publications

References 26 publications

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

Cell‐type specific activation of p38 and ERK mediates calcitonin gene‐related peptide involvement in tolerance to morphine‐induced analgesia

Selective Mediation of Nerve Injury-Induced Tactile Hypersensitivity by Neuropeptide Y

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