Articles: hyperalgesia.
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Approximately 70% of male rats receiving severe T8 spinal contusions develop allodynia in T5-7 dermatomes (at-level) beginning 2 weeks after injury. In contrast, rats having either complete transections or dorsal hemisections do not develop allodynia at-level after chronic spinal cord injury (SCI). In the present study, incomplete laceration and contusion injuries were made to test for neuroanatomical correlates between areas of white matter damage/sparing at the lesion epicenter and the presence/absence of allodynia. After incomplete laceration lesions and 6 weeks of behavioral testing, histological reconstruction and analysis of the lesion epicenters revealed a significant difference (P < .001) in the amount of ventrolateral funiculus (VLF) asymmetry between rats showing pain-like responses evoked by touch (74.5% +/- 8.4% side-to-side difference in VLF damage) versus those not responding to touch (11.3% +/- 4.4% side-to-side difference in VLF damage). A 5-week mean allodynia score for each rat that incorporates a full range of forces that are all innocuous in intact controls revealed that the degree of hypersensitivity at level is related to the extent of VLF asymmetry after SCI. No other damaged spinal white matter or gray matter area was correlated with sensitivity to touch. Similar findings were obtained for rats receiving T8 contusions, a more clinically relevant injury. These data suggest that different extents of damage/sparing between the 2 sides of VLF probably are a requisite for the development of allodynia after SCI. ⋯ A side-to-side lesion asymmetry after chronic SCI in a rodent model was found to be highly correlated with the presence and degree of allodynia. Greater insight of key factors contributing to the development and maintenance of chronic neuropathic pain is important for improving quality of life.
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J. Pharmacol. Exp. Ther. · Sep 2010
The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice.
Both delta-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. In wild-type (WT) mice at 21 days after chronic constriction of sciatic nerve, we evaluated the effects of [d-Pen(2),d-Pen(5)]-enkephalin (DPDPE); (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH-015); and a NOS1 [N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidine tris(trifluoroacetate) salt; NANT], NOS2 [l-N(6)-(1-iminoethyl)-lysine; l-NIL], l-guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ], or PKG [(Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs] inhibitor administered alone or combined. ⋯ The subplantar administration of NANT, l-NIL, ODQ, or Rp-8-pCPT-cGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.
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The study analyzes the chemical composition of the essential oil obtained from the leaves of Ugni myricoides (Kunth) O. Berg (U. myricoides EO). The composition of the essential oil was characterized by GC-FID and GC-MS analysis, showing at least six major constituents: α-pinene (52.1%), 1,8-cineole (11.9%), α-humulene (4.6%), caryophyllene oxide + globulol (4.5%), humulene epoxide II (4.2%) and β-caryophyllene (2.9%). ⋯ Repeated treatment with U. myricoides EO (5-25 mg/kg, p.o.), α-pinene (5-50 mg/kg, p.o.), or gabapentin (70 mg/kg, p.o.) also abolished the mechanical sensitization induced by CFA, or following the partial ligation of the sciatic nerve (PLSN). The present results indicate that U. myricoides EO produces marked anti-hypernociceptive effects in carrageenan and CFA mechanical sensitization models, and also inhibited neuropathic pain-like behavior after PLSN with efficacy similar to that observed for indomethacin or gabapentin. The relevant effects shown by U. myricoides EO are related, at least in part, to the presence of α-pinene and may be of potential interest for the management of inflammatory and neuropathic pain.
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Chronic pain associated with inflammation is a major clinical problem, but the underlying mechanisms are incompletely understood. Recently, we reported that GRK2(+/-) mice with a approximately 50% reduction of GRK2 develop prolonged hyperalgesia following a single intraplantar injection of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Here we show that spinal microglia/macrophage GRK2 is reduced during chronic inflammation-induced hyperalgesia. ⋯ These data establish that chronic inflammatory hyperalgesia is associated with reduced GRK2 in microglia/macrophages and that low GRK2 in these cells is sufficient to markedly prolong hyperalgesia after a single intraplantar injection of IL-1beta. Ongoing hyperalgesia is maintained by spinal microglial/macrophage activity, fractalkine signaling, p38 activation and IL-1 signaling. We propose that chronic inflammation decreases spinal microglial/macrophage GRK2, which prevents silencing of microglia/macrophage activity and thereby contributes to prolonged hyperalgesia.
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J. Pharmacol. Exp. Ther. · Sep 2010
Monoamine-dependent, opioid-independent antihypersensitivity effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a postoperative pain model in rats.
The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. ⋯ Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.