Unveiling the link between chronic pain and misuse of opioids and cannabis.

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse. However, the causal effect between chronic pain and the development of SUDs has not been clearly established. In this review, we discuss evidence that affirms the proposition that chronic pain is a risk factor for the development of opioid and cannabis use disorders by outlining the clinical evidence and detailing neurobiological mechanisms that link pain and drug misuse. Central to the link between chronic pain and opioid and cannabis misuse is hypodopaminergic transmission and the modulation of dopamine signaling in the mesolimbic pathway by opioids and cannabis. Moreover, we discuss the role of kappa opioid receptor activation and neuroinflammation in the context of dopamine transmission, their contribution to opioid and cannabis withdrawal, along with potential new treatments.

Neuroinflammation drives sex-dependent effects on pain and negative affect in a murine model of repeated mild traumatic brain injury.

ABSTRACT: The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

Optogenetic Stimulation of Midbrain Dopamine Neurons Produces Striatal Serotonin Release.

Targeting neurons with light-driven opsins is widely used to investigate cell-specific responses. We transfected midbrain dopamine neurons with the excitatory opsin Chrimson. Extracellular basal and stimulated neurotransmitter levels in the dorsal striatum were measured by microdialysis in awake mice. Optical activation of dopamine cell bodies evoked terminal dopamine release in the striatum. Multiplexed analysis of dialysate samples revealed that the evoked dopamine was accompanied by temporally coupled increases in striatal 3-methoxytyramine, an extracellular dopamine metabolite, and in serotonin. We investigated a mechanism for dopamine-serotonin interactions involving striatal dopamine receptors. However, the evoked serotonin associated with optical stimulation of dopamine neurons was not abolished by striatal D1- or D2-like receptor inhibition. Although the mechanisms underlying the coupling of striatal dopamine and serotonin remain unclear, these findings illustrate advantages of multiplexed measurements for uncovering functional interactions between neurotransmitter systems. Furthermore, they suggest that the output of optogenetic manipulations may extend beyond opsin-expressing neuronal populations.

Simultaneous serotonin and dopamine monitoring across timescales by rapid pulse voltammetry with partial least squares regression.

Many voltammetry methods have been developed to monitor brain extracellular dopamine levels. Fewer approaches have been successful in detecting serotonin in vivo. No voltammetric techniques are currently available to monitor both neurotransmitters simultaneously across timescales, even though they play integrated roles in modulating behavior. We provide proof-of-concept for rapid pulse voltammetry coupled with partial least squares regression (RPV-PLSR), an approach adapted from multi-electrode systems (i.e., electronic tongues) used to identify multiple components in complex environments. We exploited small differences in analyte redox profiles to select pulse steps for RPV waveforms. Using an intentionally designed pulse strategy combined with custom instrumentation and analysis software, we monitored basal and stimulated levels of dopamine and serotonin. In addition to faradaic currents, capacitive currents were important factors in analyte identification arguing against background subtraction. Compared to fast-scan cyclic voltammetry-principal components regression (FSCV-PCR), RPV-PLSR better differentiated and quantified basal and stimulated dopamine and serotonin associated with striatal recording electrode position, optical stimulation frequency, and serotonin reuptake inhibition. The RPV-PLSR approach can be generalized to other electrochemically active neurotransmitters and provides a feedback pipeline for future optimization of multi-analyte, fit-for-purpose waveforms and machine learning approaches to data analysis.