New pharmacological perspectives and therapeutic options for opioids: Differences matter.

Opioids remain the major drug class for the treatment of acute, chronic and cancer pain, but have major harmful effects such as dependence and opioid-induced ventilatory impairment. Although no new typical opioids have come onto the market in the past almost 50 years, a plethora of new innovative formulations has been developed to meet the clinical need. This review is intended to shed light on new understanding of the molecular pharmacology of opioids, which has arisen largely due to the genomic revolution, and what new drugs may become available in the coming years. Atypical opioids have and are being developed which not only target the mu opioid receptor but other targets in the pain pathway. Biased mu agonists have been developed but remain 'unbiased' clinically. The contribution of drugs targeting non-mu opioid receptors either alone or as heterodimers shows potential promise but remains understudied. That gene splice variants of the mu opioid receptor produce multiple receptor isoforms in different brain regions, and may change with pain chronicity and phenotype, presents new challenges but also opportunities for precision pain medicine. Finally, that opioids also have pro-inflammatory effects not aligned with mu opioid receptor binding affinity implicates a fresh understanding of their role in chronic pain, whether cancer or non-cancer. Hopefully, a new understanding of opioid analgesic drug action may lead to new drug development and better precision medicine in acute and chronic pain relief with less patient harm.

Evaluation of miRNA as Biomarkers of Emotional Valence in Pigs.

The ability to assess the welfare of animals is dependent on our ability to accurately determine their emotional (affective) state, with particular emphasis being placed on the identification of positive emotions. The challenge remains that current physiological and behavioral indices are either unable to distinguish between positive and negative emotional states, or they are simply not suitable for a production environment. Therefore, the development of novel measures of animal emotion is a necessity. Here we investigated the efficacy of microRNA (miRNA) in the brain and blood as biomarkers of emotional state in the pig. Female Large White × Landrace pigs (n = 24) were selected at weaning and trained to perform a judgment bias test (JBT), before being exposed for 5 weeks to either enriched (n = 12) or barren housing (n = 12) conditions. Pigs were tested on the JBT once prior to treatment, and immediately following treatment. MiRNA and neurotransmitters were analyzed in blood and brain tissue after euthanasia. Treatment had no effect on the outcomes of the JBT. There was also no effect of treatment on miRNA expression in blood or the brain (FDR p > 0.05). However, pigs exposed to enriched housing had elevated dopamine within the striatum compared to pigs in barren housing (p = 0.02). The results imply that either (a) miRNAs are not likely to be valid biomarkers of a positive affective state, at least under the type of conditions employed in this study, or (b) that the study design used to modify affective state was not able to create differential affective states, and therefore establish the validity of miRNA as biomarkers.

Minocycline attenuates 3,4-methylenedioxymethamphetamine-induced hyperthermia in the rat brain.

Hyperthermia is most dangerous clinical symptom of acute MDMA administration, and a key factor related to potentially life-threatening MDMA-induced complications. MDMA induces a consistently faster onset of brain hyperthermia when compared to a delayed and moderate hyperthermia in the body, and the most harmful effects of MDMA are related to its modulation of neural functions. The primary focus of this study was to investigate the effects of minocycline, a centrally acting tetracycline derivative on MDMA-induced brain hyperthermia at high ambient temperature. However, we also simultaneously recorded body temperature, heart rate, and locomotor activity changes, allowing us to gain a better understanding of the mechanisms underlying the MDMA-induced hyperthermic response. We also investigated the effects of MDMA at normal ambient temperature to provide further evidence as to the importance of environmental factors on the intensity of MDMA's temperature effects. At normal ambient temperature, MDMA (10 mg/kg, i.p.) induced a significant brain and body hypothermia for the first 90 min following drug administration, and significantly increased heart rate and locomotor activity compared to saline controls. At high ambient temperature however, MDMA (10 mg/kg, i.p.) induced a robust and extended brain and body hyperthermia, as well as significantly increased heart rate and locomotor activity. A 3-day minocycline (50 mg/kg, i.p.) pre-treatment significantly attenuated MDMA-induced increases in brain temperature, body temperature, heart rate, and locomotor activity. Our findings indicate that minocycline is more effective in attenuating the exacerbated MDMA-induced hyperthermic response in the brain compared to the body at high ambient temperature.

Improved method for optical fiber temperature probe implantation in brains of free-moving rats.

BACKGROUND: The localized monitoring of brain temperature is crucial to the understanding of the mechanisms underlying brain hyperthermia, such as that caused by stimulant drugs. Many animal studies investigating brain hyperthermia have utilized thermocouple electrodes for temperature measurement, however optical fiber sensors have proven to be an attractive alternative to conventional measurement techniques. Despite their advantages, optical fiber sensors in their current form have struggled to find effective use in studies involving free-moving animals. NEW METHOD: We have developed an improved optical fiber temperature probe and implantation method suitable for sensing in free-moving animals. By altering the structure of the probe, conventional guide cannulae can be used for stereotaxic implantation thus increasing ease-of-use and probe durability. RESULTS: The new probe structure was easily implanted and extremely durable both pre-experimentation and during sampling in vivo. Probe re-usability also allowed for increased experimental workflow. Rats administered MDMA showed pathological increases in brain temperature. COMPARISON WITH EXISTING METHOD(S): Thermocouples commonly used for temperature measurement in deep brain structures lack the advantages offered by optical fiber sensors. Unlike our improved design, previous optical fiber temperature probes were unable to be removed from the brains of rats without removing the dental cement affixing it to the skull. This made the probe susceptible to breakage and often resulted in the complete loss of the animal from the experiment. CONCLUSIONS: Our fiber temperature probe and revised implantation technique can be easily employed in brain thermorecording using advantageous optical fiber sensors suitable for use in awake free-moving animals.

Miniaturized single-fiber-based needle probe for combined imaging and sensing in deep tissue.

The ability to visualize structure while simultaneously measuring chemical or physical properties of a biological tissue has the potential to improve our understanding of complex biological processes. We report the first miniaturized single-fiber-based imaging+sensing probe capable of simultaneous optical coherence tomography (OCT) imaging and temperature sensing. An OCT lens is fabricated at the distal end of a double-clad fiber, including a thin layer of rare-earth-doped tellurite glass to enable temperature measurements. The high refractive index of the tellurite glass enables a common-path interferometer configuration for OCT, allowing easy exchange of probes for biomedical applications. The simultaneous imaging+sensing capability is demonstrated on rat brains.

Portable optical fiber probe for in vivo brain temperature measurements.

This work reports on the development of an optical fiber based probe for in vivo measurements of brain temperature. By utilizing a thin layer of rare-earth doped tellurite glass on the tip of a conventional silica optical fiber a robust probe, suitable for long-term in vivo measurements of temperature can be fabricated. This probe can be interrogated using a portable optical measurement setup, allowing for measurements to be performed outside of standard optical laboratories.