Genetic deletion of TRPA1 receptor attenuates amyloid beta- 1-42 (Aß1-42)-induced neurotoxicity in the mouse basal forebrain in vivo.

Amyloid ß 1-42 peptide (Aß1-42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aß1-42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1-/-) mice. Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss. Aß1-42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1-/- animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aß1-42-injected TRPA1+/+ mice, but not in TRPA1-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aß1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aß1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models.

Arthritic diseases are the most frequent causes of chronic pain and disability. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive structural joint damage. Osteoarthritis is a degenerative process of the articular cartilage associated with hypertrophic changes in the bone. The aim of the present study was to investigate the anti-inflammatory and analgesic effects of Hévíz thermal water and mud in monosodium iodoacetate- (MIA-) (25 mg/ml, 20 µl i.a.) induced osteoarthritis and Complete Freund's adjuvant- (CFA-) (1 mg/ml, 50-50 µl s.c) induced rheumatoid arthritis murine models. The mechanonociceptive threshold of female NMRI mice (n=6- 8 mice/ group) was measured by aesthesiometry, and paw volume was monitored with plethysmometry, knee joint diameter with digital micrometer, and dynamic weight bearing on the hind limbs with a Bioseb instrument. Periarticular bone destruction was assessed by SkyScan 1176 in vivo micro-CT. Inflammatory cytokines were detected by ELISA in plasma samples. Treatments (30 min, every working day) with tap water, sand, and a combined therapy of tap water and sand served as controls. Hévíz medicinal water and combined treatment with water and mud significantly decreased the mechanical hyperalgesia and knee oedema in MIA-induced osteoarthritis model. However, balneotherapy did not influence mechanical hyperalgesia, weight bearing, or oedema formation induced by CFA. Neither medicinal water nor mud treatment ameliorated deep structural damage of the bones or the joints in the animal models. On the basis of the present findings, we conclude that balneotherapy is an effective complementary treatment to reduce the pain sensation and swelling in degenerative joint diseases such as osteoarthritis. Our experimental data are in agreement with the previous human studies that also confirmed antinociceptive and anti-inflammatory effects of thermal water and Hévíz mud treatments.

Chronic stress-induced mechanical hyperalgesia is controlled by capsaicin-sensitive neurones in the mouse.

BACKGROUND: Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes. METHOD: Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements. RESULTS: Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production. CONCLUSIONS: Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic changes. SIGNIFICANCE: These are the first data demonstrating the complex interactions between capsaicin-sensitive neurones and chronic stress and their impact on nociception. Capsaicin-sensitive neurones are protective against stress-induced mechanical hyperalgesia by influencing neuronal plasticity in the brain.

Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception.

Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated through proteolytic cleavage. It is localized on epithelial, endothelial and inflammatory cells, as well as on transient receptor potential vanilloid 1 (TRPV1) receptor-expressing neurones. It plays an important role in inflammatory/nociceptive processes. Since there are few reports concerning PAR-2 function in joints, the effects of intraarticular PAR-2 activation on joint pain and inflammation were studied. Secondary hyperalgesia/allodynia, spontaneous weight distribution, swelling and inflammatory cytokine production were measured and the involvement of TRPV1 ion channels was investigated in rats and mice. Injection of the PAR-2 receptor agonist SLIGRL-NH(2) into the knee decreased touch sensitivity and weight bearing of the ipsilateral hindlimb in both species. Secondary mechanical allodynia/hyperalgesia and impaired weight distribution were significantly reduced by the TRPV1 antagonist SB366791 in rats and by the genetic deletion of this receptor in mice. PAR-2 activation did not cause significant joint swelling, but increased IL-1beta concentration which was not influenced by the lack of the TRPV1 channel. For comparison, intraplantar SLIGRL-NH(2) evoked similar primary mechanical hyperalgesia and impaired weight distribution in both WT and TRPV1 deficient mice, but oedema was smaller in the knockouts. The inactive peptide, LRGILS-NH(2), injected into either site did not induce any inflammatory or nociceptive changes. These data provide evidence for a significant role of TRPV1 receptors in secondary mechanical hyperalgesia/allodynia and spontaneous pain induced by PAR-2 receptor activation in the knee joint. Although intraplantar PAR-2 activation-induced oedema is also TRPV1 receptor-mediated, primary mechanical hyperalgesia, impaired weight distribution and IL-1beta production are independent of this channel.