A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) ...system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.
Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The ...combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.
Here, we examined the impact of chronic (3-month) HIV-1 transactivator of transcription (Tat) exposure to short-term (8-day), escalating morphine in HIV-1 Tat transgenic mice that express the HIV-1 Tat protein in a GFAP promoter-regulated, doxycycline (DOX)-inducible manner. In addition to assessing morphine-induced tolerance in nociceptive responses organized at spinal (i.e., tail-flick) and supraspinal (i.e., hot-plate) levels, we evaluated neuroinflammation via positron emission tomography (PET) imaging using the
F-PBR111 ligand, immunohistochemistry, and cytokine analyses. Further, we examined endocannabinoid (eCB) levels, related non-eCB lipids, and amino acids via mass spectrometry. RESULTS: Tat-expressing Tat(+) transgenic mice displayed antinociceptive tolerance in the tail withdrawal and hot-plate assays compared to control mice lacking Tat Tat(-). This tolerance was accompanied by morphine-dependent increases in Iba-1 ± 3-nitrotryosine immunoreactive microglia, and alterations in pro- and anti-inflammatory cytokines, and chemokines in the spinal cord and striatum, while increases in neuroinflammation were absent by PET imaging of
F-PBR111 uptake. Tat and morphine exposure differentially affected eCB levels, non-eCB lipids, and specific amino acids in a region-dependent manner. In the striatum, non-eCB lipids were significantly increased by short-term, escalating morphine exposure, including peroxisome proliferator activator receptor alpha (PPAR-α) ligands N-oleoyl ethanolamide (OEA) and N-palmitoyl ethanolamide (PEA), as well as the amino acids phenylalanine and proline. In the spinal cord, Tat exposure increased amino acids leucine and valine, while morphine decreased levels of tyrosine and valine but did not affect eCBs or non-eCB lipids.
Overall results demonstrate that 3 months of Tat exposure increased morphine tolerance and potentially innate immune tolerance evidenced by reductions in specific cytokines (e.g., IL-1α, IL-12p40) and microglial reactivity. In contrast, short-term, escalating morphine exposure acted as a secondary stressor revealing an allostatic shift in CNS baseline inflammatory responsiveness from sustained Tat exposure.
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•Co-exposure to HIV-1 Tat and morphine increased striatal tau phosphorylation.•Morphine exposure increased tau phosphorylation in the prefrontal cortex.•HIV-1 Tat exposure increased ...tau phosphorylation in the hippocampus and striatum.•Interactive tauopathy induced by Tat and morphine resembles accelerated brain aging.•Tat and morphine may selectively phosphorylate specific pathologic tau epitopes.
Opiate abuse is prevalent among HIV-infected individuals and may exacerbate HIV-associated age-related neurocognitive disorders. However, the extent to which HIV and opiates converge to accelerate pathological traits indicative of brain aging remains unknown. The pathological phospho-isotypes of tau (pSer396, pSer404, pThr205, pSer202, and pThr181) and the tau kinases GSK3β and CDK5/p35 were explored in the striatum, hippocampus, and prefrontal cortex of inducible male and female HIV-1 Tat-transgenic mice, with some receiving escalating doses of morphine for 2 weeks. In the striatum of male mice, pSer396 was increased by co-exposure to morphine and Tat as compared to all other groups. Striatal pSer404 and pThr205 were increased by Tat alone, while pSer202 and pThr181 were unchanged. A comparison between Tat-transgenic female and male mice revealed disparate outcomes for pThr205. No other sex-related changes to tau phosphorylation were observed. In the hippocampus, Tat increased pSer396, while other phosphorylation sites were unchanged and pSer202 was not detected. In the prefrontal cortex, morphine increased pSer396 levels, which were unaffected by Tat, while other phosphorylation sites were unaffected. Assessment of tau kinases revealed no changes to striatal GSK3β (phosphorylated or total) or the total CDK5 levels. Striatal levels of phosphorylated CDK5 and p35, the activator of CDK5, were increased by Tat and with morphine co-exposure, respectively. P35 levels positively correlated with those of pSer396 with Tat and morphine co-exposure. The results reveal region-specific hyperphosphorylation of tau induced by exposure to morphine, Tat, and unique morphine and Tat interactions.
•THC withdrawal increases plasma corticosterone levels.•THC or JWH-018 withdrawal increases struggling in the tail suspension test.•THC or JWH-018 withdrawal suppresses marble ...burying.•Monoacylglycerol lipase (MAGL) inhibition attenuates THC withdrawal.•THC withdrawal is induced spontaneously, during abstinence.
A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence.
C57BL/6 J mice were repeatedly administered the phytocannabinoid Δ9-tetrahydrocannabinol (THC; 1, 10 or 50 mg/kg, s.c.), the synthetic cannabinoid receptor agonist JWH-018 (1 mg/kg, s.c.), or vehicle (1:1:18 parts ethanol:Kolliphor EL:saline, s.c.) for 6 days. Withdrawal was precipitated with the cannabinoid receptor inverse agonist rimonabant (3 mg/kg, i.p.) or elicited via abstinence (i.e., spontaneous withdrawal), and putative stress-related behavior was scored. Classic somatic signs of cannabinoid withdrawal were also quantified.
Precipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24–48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors.
Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.
Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain ...circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing-activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.
Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically worsen neuroHIV. Despite the advent of combined antiretroviral therapies (cART), about half ...of persons infected with HIV (PWH) experience cognitive and emotional deficits that can be exacerbated by opioid abuse. HIV-1 Tat is expressed in the central nervous system (CNS) of PWH on cART and is thought to contribute to neuroHIV. The amygdala regulates emotion and memories associated with fear and stress and is important in addiction behavior. Notwithstanding its importance in emotional saliency, the effects of HIV and opioids in the amygdala are underexplored. To assess Tat- and morphine-induced neuropathology within the amygdala, male Tat transgenic mice were exposed to Tat for 8 weeks and administered saline and/or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of Tat exposure. Eight weeks of Tat exposure decreased the acoustic startle response and the dendritic spine density in the basolateral amygdala, but not the central nucleus of the amygdala. In contrast, repeated exposure to morphine alone, but not Tat, increased the acoustic startle response and whole amygdalar levels of amyloid-β (Aβ) monomers and oligomers and tau phosphorylation at Ser396, but not neurofilament light chain levels. Co-exposure to Tat and morphine decreased habituation and prepulse inhibition to the acoustic startle response and potentiated the morphine-induced increase in Aβ monomers. Together, our findings indicate that sustained Tat and morphine exposure differentially promote synaptodendritic degeneration within the amygdala and alter sensorimotor processing.
Despite the advent of combination anti‐retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV‐associated neurocognitive disorders (HAND). HAND can be ...worsened by co‐morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV‐1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co‐exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co‐exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety‐like, novelty‐seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5‐hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase‐positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context‐dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty‐seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time‐dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV‐1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.
To examine the relationship between opioid and HIV‐1‐induced alterations in striatal monoamine concentrations and behavior, morphine was administered to HIV‐1 Tat transgenic mice for 2 weeks or 2 months. Morphine and Tat interacted to alter levels of dopamine, dopamine metabolites, norepinephrine, and 5‐hydroxyindoleacetic acid depending on the duration of exposure and neurotransmitter/metabolite assayed. Co‐exposure to Tat and morphine disrupted locomotor activity in a time‐dependent manner. Alternatively, Tat alone inhibited social exploratory behavior, whereas morphine alone tended to increase novelty‐seeking behavior. The data suggest that Tat and morphine effects on monoamine neurochemistry are complex and contribute to motor and exploratory behavioral dysregulation.
Cover image for this issue: https://doi.org/10.1111/jnc.15855
•Tat decreases dendritic spines throughout the hippocampal trisynaptic pathway.•Tat selectively decreases apical spines in granule, and CA3 and CA1 pyramidal cells.•The density of apical spines in ...the trisynaptic circuit are unaffected by morphine.
Nearly one-third of persons infected with HIV-1 (PWH) develop HIV-associated neurocognitive disorders (HAND), which can be exacerbated by exposure to opioids. The impact of opioids on HIV-induced alterations in neuronal plasticity is less well understood. Both morphine exposure and HIV have been shown to disrupt synaptic growth and stability in the hippocampus suggesting a potential site of convergence for their deleterious effects. In the present study, we examined the density of dendritic spines in CA1 and CA3 pyramidal neurons, and granule neurons within the dentate gyrus representing the hippocampal trisynaptic pathway after short-term exposure to the HIV transactivator of transcription (Tat) protein and morphine. We exposed inducible male, HIV-1 Tat transgenic mice to escalating doses of morphine (10–40 mg/kg, b.i.d.) and examined synaptodendritic structure in Golgi-impregnated hippocampal neurons. HIV-1 Tat, but not morphine, systematically reduced the density of apical, but not basilar, dendrites of CA1 and CA3 pyramidal neurons, and granule neuronal apical dendrites, suggesting the coordinated loss of specific synaptic interconnections throughout the hippocampal trisynaptic pathway.
Abstract The physiological and behavioral effects of stress are well characterized. Endocannabinoids are produced on demand and function to attenuate many of the physiological effects of the stress ...response. The endocannabinoid system is made up of cannabinoid receptors, the fatty acid signaling molecules that bind to and activate these receptors, and the enzymes that synthesize and catabolize these endocannabinoid signaling molecules. Cannabinoid research has recently grown substantially, due in no small part to the development of genetic research models as well as highly selective pharmaceutical tools. The purpose of this minireview is to discuss a subset of the many parallels between cannabinoid and behavioral neuroimmunology research, with specific discussion of interactions between the endocannabinoid system and psychological stress, emotionality, and inflammation.
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