We propose a method to estimate fibre length distribution in conifers based on wood samples from
increment cores processed by automatic optical fibre-analysers. Automatic fibre-analysers are unable
to distinguish: a) fibres from other tissues, “fines”, and b) cut from uncut fibres. However, our
proposed method can handle these problems if the type of distributions that fibre lengths and fines
follow is known. In our study the length distributions of fines and fibres were assumed to follow
truncated normal distributions, characterised by means and standard deviations of the two distributions.
Parameter estimates were obtained by the maximum likelihood method. Wood samples
from two 22-year-old Scots pine trees at breast height were used to evaluate the performance of
the method. From stem discs at 1.5 m, adjacent samples of 5 mm increment cores and wood pieces
were taken. The cores were trimmed 1 mm at each side and samples were, after maceration,
analysed in a Kajaani FiberLab 3.0. The results showed that the method works well and gives a
possibility to distinguish fine and fibre length distribution.
Arthritis is the leading cause of chronic pain in European adults (painineurope.com). Arthritis-induced chronic pain is a major clinical problem that is frequently inadequately treated by current analgesics and results in significant reduction in the patient’s quality of life. Outcome measures used in pain research to assess injury-induced pain-like behaviours in preclinical models are often dependent on the assessment of withdrawal reflexes, typically evoked by mechanical or thermal stimuli.Advances inpre-dictive validity may be improved by assessing the global impact of pain and the reinstatement of innate behaviours suppressed by injury. Burrowing, an indicator of the global “wellbeing” of the animal can be objectively measured. We aimed to assess the impact of several preclinical modelsof arthritis onburrowing behaviour in mice.
The collagen antibody-induced arthritis (CAIA) pre-clinical model of rheumatoid arthritis, the complete Freund’s adjuvant (CFA), monosodium iodoacetate (MIA) and partial medial menisectomy (MMT) preclinical models of osteoarthritis were assessed in female and/or male C57/Black6J adult mice, comparing to control (salineorsham-operated) and naïve animals. Mechanical hypersensitivity using von Frey filaments and spontaneous burrowing behaviour were assessed over60days (CAIA), 14days (CFA), 28 days (MIA) and up to 200 days (MMT).
We show the development of mechanical hypersen-sitivity in all preclinical models of arthritis, whereas spontaneous burrowing behaviour was altered differently between the preclin-ical models. A deficit in burrowing behaviour was observed in the preclinical models of osteoarthritis and a gain in burrowing behaviour noted in the preclinical model of rheumatoid arthritis, with no effect seen in the CFA model.
Burrowing behaviour appears more sensitive to detecting variation in preclinical models of arthritis when compared to mechanical hypersensitivity. Burrowing behaviour can detect both gain and deficits in the behaviour, which differs between preclinical models of rheumatoid and osteoarthritis.
Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in patients with neuropathic pain syndromes such as postherpetic neuralgia, though its efficacy is controversial. After the publication of two randomized clinical trials in postherpetic neuralgia patients treated with similar intrathecal methylprednisolone acetate (MPA) dosing regimes with conflicting results; one showing significant pain reduction (Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;23: 1514–9), the other increased pain sensations (Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ: No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;38:175–200), we decided additional research was warranted. Present study sought to determine effects of intrathecally delivered methylprednisolone on pain-like behaviour and pain-associated markers in three well established rodent pain models: (1) intraplantar carrageenan, (2) intraplantar formalin, and (3) ligation of L5/L6 spinal nerves (SNL model).
Male rats with intrathecal catheters were examined for (1) tactile allodynia after unilateral hindpaw intraplantar carrageenan injection (2%), (2) flinching and subsequent long term tactile allodynia after unilateral hindpaw intraplantar formalin injection (2.5%) or (3) tactile allodynia after unilateral ligation of the L5 and L6 spinal nerves. Rats were treated with the maximum tolerable intrathecal dose of the soluble methylprednisolone sodium succinate (MP) or the particulate methylprednisolone acetate (MPA). Dorsal root ganglia and spinal cords were harvested for immunohistochemistry to assess markers of neuronal damage (ATF3) and glial activation (GFAP, Iba1).
During dose finding, severe generalized allodynia was observed with high intrathecal doses of both MPA and MP in naive rats. MPA had no effect upon tactile allodynia after carrageenan. MP and MPA did not reverse tactile allodynia in the SNL model, and did not reduce flinching in the formalin model. MP and MPA prevented the delayed (7–day) tactile allodynia otherwise observed in the formalin-injected paw. Systemic MP or perineural MP or MPA did not reduce pain-like behaviour in the SNL model. No reduction of neuronal injury (ATF3) in the dorsal root ganglion or astrocyte activation (GFAP) in the spinal dorsal horn with intrathecal MP or MPA was observed. There was a decrease in microglial activation (Iba1) in the spinal dorsal horn with MPA after SNL.
Severe generalized allodynia was observed after high intrathecal doses of MP and MPA in naive rats. No acute analgesic effects with intrathecal glucocorticoids were observed in three well established pain models. Only a late antiallodynic effect was present in the formalin model, 7 days after formalin injection and drug treatment.
Our results do not support use of intrathecal methylprednisolone in the treatment of pain.
We have previously reported that sinomenine, an alkaloid isolated from the root of the plant Sinomenium acutum, had antinociceptive effect in rodent models of acute inflammatory or neuropathic pain. As a traditional medicine, sinomenine is used in China to treat rheumatoid arthritis (RA).
In the present study, we evaluated the potential antinociceptive effect of sinomenine in a mouse model of RA, collagen type II antibody (CII Ab) induced arthritis (CAIA) after acute and chronic administration.
As single administration, sinomenine at 40 or 80 mg/kg significantly reduced mechanical hypersensitivity both at the time of peak joint inflammation (days 11–19 after CII Ab injection) or during the post-inflammatory phase (days 35–54). No tolerance to the effect of 80 mg/kg sinomenine was observed during repeated injection twice a day for 5 days from day 11 to day 19 or from day 49 to day 53 after CII Ab injection in CAIA mice.
We have shown that sinomenine is effective in alleviating localized and spread hypersensitivities in CAIA mice both during acute inflammation and in post-inflammatory phase. Further, repeated sinomenine administration has elevated the baseline mechanical threshold without producing tolerance.
Sinomenine may be clinically useful to treat chronic pain in RA, including wide-spread pain which appears to be a difficult clinical problem despite the improvement in the acute treatment of RA by disease modifying agents.
The lysophosphatidic acid (LPA) is an important mediator involved in neuropathic and bone cancer pain models. We are investigating if LPA is involved in arthritis-induced pain in the collagen antibody-induced arthritis (CAIA) mice model.
Arthritis was induced in male CBA mice by injection of 1.5 mg collagen type II antibody cocktail. Mechanical and thermal sensitivity and the degree of arthritis were assessed with von Frey filaments, Hargreaves box (heat), acetone test (cold) and visual scoring, respectively. LPA antibody and control IgG (10mg/kg), or saline was injected s.c. twice a week from day 12 through day 47. qPCR and immunohistochemical studies were undertaken in dorsal root ganglia (DRGs) to explore the expression of pain-related ion channels.
Administration of LPA antibody treatment reversed CAIA-induced mechanical and thermal hypersensitivity (p < 0.05) while had no effect on the early clinical signs of arthritis (p > 0.05). mRNA levels for the LPA synthesizing enzyme autotaxin were elevated in the CAIA group. On day 48, expression of the voltage-gated calcium channel Cavα2δ1 and the ATP-gated P2X3 receptor were significantly increased in the CAIA DRGs, which were completely prevented by LPA antibody treatment. Of note, based on in vitro experiment, LPA stimulation upregulated Cavα2δ1 and P2X3 expression in primary adult mouse DRG cultures.
Blocking the action of systemic LPA reverses arthritis-induced hypersensitivity, potentially through regulation of Cavα2δ1 and P2X3 expression in peripheral neurons. Thus, our data point to that LPA may serve as a target for providing pain relief in arthritis.
Despite widespread use, the efficacy of neuraxial glucocorticoids for neuropathic painis subject to debate. Since most glucocorticoid actions are mediated through its receptor, we explored the effects of intrathecal methylprednisolone acetate (MPA) on total glucocorticoid receptor (tGR) levels and activation of the glucocorticoid receptor (phosphorylated state = pGR) within the spinal dorsal horn (SDH) and dorsal root ganglion (DRG) in a spinal nerve ligation (SNL) model in rats.
Rats received unilateral ligation of the L5/L6 spinal nerves and were treated with two intrathecal doses of either 400 μg MPA or 0.9% saline with a 72-h interval. Plantar tactile thresholds were measured over time. Seven days after drug treatment, DRG and SDH were harvested to assess tGR and pGR levels using immunohistochemistry and qPCR.
Allodynia, defined by lowered tactile withdrawal thresholds after SNL, was unaltered by intrathecal MPA. In saline controls, mRNA levels of tGR did not change after SNL in the DRGs or SDH. tGR and pGR protein levels in the SDH however, significantly increased on the ipsilateral side of SNL compared to the contralateral side and to naïve tissue. When treating rats with MPA, tGR mRNA levels were significantly reduced in the SDH compared to saline controls. tGR and pGR protein levels, however were not significantly lower compared to saline controls.
In intrathecal MPA treated rats, tGR mRNA levels decreased after SNL. However this did not result in lower tGR and pGR protein levels compared to saline controls, and did not decrease ligation-induced mechanical hypersensitivity.
Intrathecal MPA treatment after SNL did not result in lower tGR and pGR levels within the SDH and DRG compared to saline controls. In present study we did not differentiate between the various isoforms of the GR which might clarify this finding.