Animal Studies

Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB/CB agonist, WIN55,212-2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [S]GTPγS assay. It was shown that WIN55,212-2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212-2. The intensity of behavioral responses to WIN55,212-2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212-2 in LA mice could depend on impaired CB receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.

Data from preclinical research has been suggested to suffer from a lack of inherent reproducibility across laboratories. The goal of our study was to replicate findings from a previous report that demonstrated positive effects of Meteorin, a novel neurotrophic factor, in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Notably, 5-6 intermittent s.c. injections of Meteorin had been reported to produce reversal of mechanical allodynia/thermal hyperalgesia post-injury wherein maximum efficacy of Meteorin was reached slowly and outlasted the elimination of the compound from the blood by several weeks. Here, we evaluated the efficacy of Meteorin in reversing hindpaw mechanical hyperalgesia and cold allodynia in male, Sprague-Dawley rats with CCI. Nociceptive behavior was monitored before and after CCI, and after drug treatment until day 42 post-injury. Systemic administration of recombinant mouse Meteorin (0.5 and 1.8 mg/kg, s.c.) at days 10, 12, 14, 17 and 19 after CCI produced a prolonged reversal of neuropathic hypersensitivity with efficacy comparable to that obtained with gabapentin (100 mg/kg, p.o.). Despite some protocol deviations (e.g. nociceptive endpoint, animal vendor, testing laboratory, investigator, etc.) being incurred these did not affect study outcome. By paying careful attention to key facets of study design, using bioactive material, and confirming drug exposure, the current data have replicated the salient findings of the previous study promoting confidence in further advancement of this novel molecule as a potential therapy for neuropathic pain.

Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain.