Spinal nerve ligation

AM1241 (360) exhibited high affinity and selectivity for CB2 [it (CBi) = 280 nM, (CB2) = 3.4 nM]. (360) Dose dependently inhibited experimental neuropathic pain in a spinal nerve ligation-induced tactile and thermal hypersensitivity model [224]. Other indole derivatives bearing sulfonamide moieties on the side chain, such as compound (361), were disclosed [225]. Though 67 derivatives including pyridyl and other heteroaromatics instead of the indole core were listed, no specific biological data were shown. 

Kim, S. H. and Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50, 355-363. 

Kim, C. H., Oh, Y., Chung, J. M., Chung, K. The changes in expression of three subtypes of TTX sensitive sodium channels in sensory neurons after spinal nerve ligation, Brain Res Mol 2001, 95, 153-161. 

Compounds with moderate p-affinities are very potent in a variety of pain models in mice and rats. In addition to antinociceptive efficacy in models of acute pain (tail flick, writhing) these compounds inhibit acute and persistent inflammatory pain (Randall Selitto, formalin test). Furthermore, they show strong inhibition of acute visceral pain (colorectal distension) and of tactile and cold allodynia in models of neuropathic pain (spinal nerve ligation (Chung), chronic constriction injury (Bennett)). The data suggest these compounds to be potential candidates for the management of clinical pain indications. Somatic and visceral pain with and without inflammatory conditions as well as neuropathic pain might be addressed with this approach. 

SNX-111, when given alone, is active in the Chung model (spinal nerve ligation), tactile allodynia test (hindpaw UV burn) and paw pressure test. In the hot plate assay there is only a small but significant effect of about 20% increase in response latency (Table 4, Malmberg and Yaksh, 1994). 

Chung model (spinal nerve ligation) SNX-111 0. 03, 0.1 and 0.3 pg 1. t. Dose-dependent blockade of mechan. allodynia in neuropathy rats Bowersox et al. (1998)... 

Jin, S. X., Zhuang, Z. Y., Woolf, C. J., andji, R. R. (2003). p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 23, 4017—4022. 

Schafers, M., Svensson, C. I., Sommer, C., and Sorkin, L. S. (2003). Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517-2521. 

Zhuang, Z. Y., Wen, Y. R., Zhang, D. R., Borsello, T., Bonny, C., Strichartz, G. R., Decosterd, I., and Ji, R. R. (2006). A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation Respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance.. Neurosci. 26, 3551 -3560. 

LINALOOL ATTENUATES ALLODYNIA IN NEUROPATHIC PAIN INDUCED BY SPINAL NERVE LIGATION IN C57/BL6 MICE... 

Linalool is a natural compound with anti-inflammatory and antinociceptive properties. The antinociceptive action of Iinalool has been reported in several models of inflammatory pain. However, its effects in neuropathic pain have not been investigated. Here, we used the spinal nerve ligation (SNL) model of... 

While the antinociceptive effect exerted by linalool has been extensively investigated in inflammatory pain, no studies exist on the effects of linalool in models of neuropathic pain. To this aim, we used the spinal nerve ligation (SNL) model of neuropathic pain (Kim and Chung, 1992) and studied the effects of acute and chronic administration of (—)-linalool on mechanical and thermal hypersensitivity induced by nerve injury in mice. 

Fig. 1. (—)-Iinalool attenuates mechanical allodynia induced by spinal nerve ligation in mice. (A and B) Mechanical allodynia developed and maintained over time following spinal nerve ligation (SNL). (A) A single dose of linalool (100 mg/kg s.c.) did not cause any significant changes compared to SNL and vehicle-treated animals. (B) Linalool administered daily for 7 days attenuated mechanical allodynia compared to SNL animals and SNL animals treated with the vehicle ( p < 0.001 vs vehicle ANOVA+Tukey test). Data are expressed as mean SEM of the value corresponding to 50% of pain threshold and are normalized to the basal value of each animal. Differences are evaluated using oneway analysis of variance (ANOVA), followed by post hoc Tukey multiple comparison tests, p < 0.05 was regarded as significant.

Fig. 5. Modulation of IL-1/3 spinal content by spinal nerve ligation and (—)-linalool. IL-1/3 content was determined by ELISA in lumbar spinal cord homogenates. Animals were sacrificed at different time points after SNL alone or in combination with linalool (100 mg/kg s.c.) and vehicle treatment (mean SEM from n — 2 3 for each experimental group).

It has been demonstrated that neuropathic pain is opioid resistant and, indeed, neither systemic nor i.t. administration of opioids reduced effectively neuropathic pain in rats (Bian et al., 1995 Lee et al., 1995 Mao et al., 1995 Ossipov et al., 1995). It seems worth to note that s.c. administration of (—) linalool attenuates mechanical allodynia in spinal nerve ligation model of neuropathic pain in mice (Levato et al., 2006). 

Vincler M, Eisenach JC (2004) Plasticity of spinal nicotinic acetylcholine receptors following spinal nerve ligation. Neurosci Res 48 139-145... 

Gold There does seem to be some disagreement on this point. The spinal nerve ligation (SNL) model is a model of nerve injury that has been used to determine whether nerve injury results in changes in Na channel expression in uninjured nerves. The sciatic nerve is comprised of axons arising from L4, L5 and L6 dorsal root ganglia. If you cut one or two of the spinal nerves, say L5 and L6, before they join the common nerve, the result is a pain syndrome with symptoms similar to... 

Strichart That is important, and it is consistent with observations from the Johns Hopkins group using spinal nerve ligation in monkeys. They have shown that hyperactivity in C fibres emanating from uninjured ganglia were elevated. Isn t this consistent with Porecca s hypothesis that elevation of PN3 is important for mechanical allodynia ... 

Ali Z, Ringkamp M, Hartke TV et al 1999 Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey. J Neurophysiol 81 455—466... 

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