Animal Studies

Cannabinoids are emerging as an alternative pain management option, preliminarily supported by preclinical and clinical studies. Unwanted side effects from oral or inhaled cannabinoids remain, however, a major barrier to widespread use. Peripherally acting cannabinoids (eg, topically applied) may circumvent these side effects while providing localized pain management.

Inflammatory and neuropathic-like components underlie rheumatoid arthritis (RA)-associated pain and lysophosphatidic acid (LPA) is linked to both joint inflammation in RA patients and to neuropathic pain. Thus, we investigated a role for LPA signalling using the collagen antibody-induced arthritis (CAIA) model. Pain-like behavior during the inflammatory phase and the late, neuropathic-like phase of CAIA was reversed by a neutralizing antibody generated against LPA and by an LPA receptor inhibitor, but joint inflammation was not affected. Autotaxin, an LPA synthesizing enzyme was upregulated in dorsal root ganglia (DRG) neurons during both CAIA phases, but not in joints or spinal cord. Late-phase pronociceptive neurochemical changes in the DRG were blocked in Lpar1 receptor deficient mice and reversed by LPA neutralization. In vitro and in vivo studies indicated that LPA regulates pain-like behavior via the LPA receptor on satellite glia cells (SGCs), which is expressed by both human and mouse SGCs in the DRG. Furthermore, CAIA-induced SGC activity is reversed by phospholipid neutralization and blocked in Lpar1 deficient mice. Our findings suggest that the regulation of CAIA-induced pain-like behavior by LPA signalling is a peripheral event, associated with the DRGs and involving increased pronociceptive activity of SGCs, which in turn act on sensory neurons.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.

Although laboratory animals experience pain as a necessary component of the objectives of experimental protocols, the level of pain should be minimized through use of an adequate analgesic regimen. The non-steroidal anti-inflammatory drug meloxicam may be beneficial in alleviating post-operative pain in mice, although no regimen has been demonstrated as universally efficacious owing to differences in experimental protocols, strain, sex, and incomplete descriptions of methodology in the literature. The aim of this systematic literature review was to identify potential applications of meloxicam for pain management in experimental mice and to evaluate the general quality of study design. Searches of MEDLINE, Scopus and CAB Direct databases elicited 94 articles published between January 2000 and April 2020 that focused on the analgesic efficacy of meloxicam in the management of momentary or persistent pain in mice. The extracted data showed that most articles were deficient in descriptions of housing, husbandry, group size calculation and humane endpoint criteria, while few described adverse effects of the drug. A wide range of dosages of meloxicam was identified with analgesic efficiencies that varied considerably according to the different models or procedures studied. It was impossible to correlate the extracted data into a single meta-analysis because of the differences in experimental protocols and strains employed, the low representation of female mice in the studies, and incomplete descriptions of the methodology applied. We conclude that meloxicam has potential application for pain management in mice but that the dosage must be adjusted carefully according to the experimental procedures. Moreover, authors must take more care in designing their studies and in describing the methodology employed.

Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease. It has a substantial impact onpatient quality of life and is a common cause of pain and mobility issues in older adults. The functional limitations, lack of curative treatments, and cost to society all demonstrate the need for translational and clinical research. The use of OA models in mice is important for achieving a better understanding of the disease. Models with clinical relevance are needed to achieve 2 main goals: to assess the impact of the OA disease (pain and function) and to study the efficacy of potential treatments. However, few OA models include practical strategies for functional assessment of the mice. OA signs in mice incorporate complex interrelations between pain and dysfunction. The current review provides a comprehensive compilation of mousemodels of OA and animal evaluations that include static and dynamic clinical assessment of the mice, merging evaluationof pain and function by using automatic and noninvasive techniques. These new techniques allow simultaneous recordingof spontaneous activity from thousands of home cages and also monitor environment conditions. Technologies such as videographyand computational approaches can also be used to improve pain assessment in rodents but these new tools must first be validated experimentally. An example of a new tool is the digital ventilated cage, which is an automated home-cage monitor that records spontaneous activity in the cages.

Whether pinocembrin (PCN) could be utilized to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from week 3 to week 4. Then hind paw mechanical allodynia, unweighting, warmth, and thickness were measured. The microglia and astrocytes activation and proliferation markers in the spinal dorsal horn were detected with real-time PCR and immunofluorescence staining. The relative expression of substance P and its receptor, tachykinin receptor 1 (Tacr1), were detected with enzyme-linked immunosorbent assay (ELISA) and Western blots. The antinociceptive effect of Tacr1 inhibitor LY303870 was also testified. PCN alleviated hip fracture-induced hind paw nociceptive (allodynia and unweighting) and vascular changes (warmth and thickness) in aged rats with diminished microglia and astrocytes activation and proliferation in the spinal dorsal horn. Up-regulated substance P and Tacr1 were induced after hip fracture, which could be reversed by PCN treatment. Furthermore, LY303870 treatment partially reversed both spinal nociceptive sensitization and vascular changes after hip fracture. Substance P signaling contributes to the nociceptive and vascular changes observed in the hip fracture, which could be alleviated by PCN.