Effects of inflammatory pain on CB1 receptor in the midbrain periaqueductal gray.

Introduction: The periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals.

Oxycodone in the Opioid Epidemic: High 'Liking', 'Wanting', and Abuse Liability.

It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis.

Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect.

Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use.

Temporal effect of manipulating NeuroD1 expression with the synthetic small molecule KHS101 on morphine contextual memory.

The treatment of opioid addiction is challenging because addicts are highly prone to relapse when the memory of the former drug experience is triggered by emotional or environmental cues. An emerging and promising concept in addiction biology is that by manipulating adult hippocampal neurogenesis, a phenomenon involved in learning and memory, drug reward-like behaviors and relapse can be attenuated. We tested a new synthetic compound, KHS101, in an animal model of drug-associated contextual memory.

Src-dependent phosphorylation of μ-opioid receptor at Tyr modulates opiate withdrawal.

Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ-opioid receptor (MOR) at Tyr by Src after prolonged opiate treatment Here, we report that the Src-mediated MOR phosphorylation at Tyr is a prerequisite for opiate withdrawal in mice.

Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo.

The development of tolerance to morphine, one of the most potent analgesics, in the management of chronic pain is a significant clinical problem and its mechanisms are poorly understood. Morphine exerts its pharmacological effects via the μ-opioid receptor (MOR). Tolerance is highly connected to G-protein-coupled receptors (GPCR) phosphorylation and desensitization increase.

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion.

Background: The opioid antagonists naloxone/naltrexone are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity.

Methods: To measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-GluA1 imaging and biochemical analyses were performed on primary hippocampal neurons.

Regulatory effect of dehydroepiandrosterone on spinal cord nociceptive function.

To characterize endogenous molecules regulating nociception, various groups have focused on dehydroepiandrosterone (DHEA). Indeed, DHEA modulates NMDA and P2X receptors which control neurobiological activities including nociception. Thus, various results were published on DHEA ability to regulate nociception but the data were interpreted separately.

Evidence for a key role of steroids in the modulation of pain.

Neurotransmitters such as glutamate, substance P, serotonin and gamma-aminobutyric acid pivotally control pain mechanisms. It is also well known that inflammatory and/or neuropathic pain may depend on the action of diverse cytokines and other molecules including eicosanoids, endorphins, calcitonin-gene related peptide, free radicals and transcription factors. Because steroids control the development, activities and plasticity of the nervous system, these compounds are of particular interest in the modulation of pain.

Biochemical and functional evidence for the control of pain mechanisms by dehydroepiandrosterone endogenously synthesized in the spinal cord.

We investigated the role and mechanism of action of dehydroepiandrosterone (DHEA) produced by the spinal cord (SC) in pain modulation in sciatic-neuropathic and control rats. Real-time polymerase chain reaction (PCR) after reverse transcription revealed cytochrome P450c17 (DHEA-synthesizing enzyme) gene repression in neuropathic rat SC. A combination of pulse-chase experiments, high performance liquid chromatography (HPLC), and flow-scintillation detection showed decreased DHEA biosynthesis from pregnenolone in neuropathic SC slices.

Assessment of neuroactive steroid formation in diabetic rat spinal cord using high-performance liquid chromatography and continuous flow scintillation detection.

The combination of pulse-chase experiments with high-performance liquid chromatography and continuous flow scintillation detection was used successfully to determine the effects of chronic diabetes on neurosteroid production in the adult rat spinal cord. The long-term diabetes was induced by treatment of adult rats with streptozotocin. In the first part, the review provides an extensive description of the HPLC combined with continuous flow scintillation detection method, its advantages and appropriateness for the question investigated.

Neurogenic pain and steroid synthesis in the spinal cord.

The spinal cord (SC) is a biosynthetic center for neurosteroids, including pregnenolone (PREG), progesterone (PROG), and 3alpha/5alpha-tetrahydroprogesterone (3alpha/5alpha-THP). In particular, an active form of cytochrome P450 sidechain cleavage (P450scc) has been localized in sensory networks of the rat SC dorsal horn (DH). P450scc is the key enzyme catalyzing the conversion of cholesterol (CHOL) into PREG, the rate-limiting step in the biosynthesis of all classes of steroids.

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: a potential component of nociception.

A crucial biochemical reaction in vertebrates is progesterone conversion into neuroactive metabolites such as dihydroprogesterone (5alpha-DHP) and tetrahydroprogesterone (3alpha,5alpha-THP), which regulate several neurobiological processes, including stress, depression, neuroprotection, and analgesia. 3alpha,5alpha-THP is a potent stimulator of type A receptors of GABA, the main inhibitory neurotransmitter. Here, we show that in the spinal sensory circuit progesterone conversion into 5alpha-DHP and 3alpha,5alpha-THP is inhibited dose-dependently by substance P (SP), a major mediator of painful signals.

Molecular and neurochemical evidence for the biosynthesis of dehydroepiandrosterone in the adult rat spinal cord.

Various studies have indicated that exogenous dehydroepiandrosterone (DHEA) modulates several mechanisms in the CNS of rodents. As adult rodent glands do not secrete significant amounts of DHEA, its role as endogenous modulator of the CNS remains possible only if DHEA is produced by nerve cells. Therefore, the last decade has been marked by diverse unsuccessful investigations aiming to demonstrate the activity of cytochrome P450c17 (P450c17), the key DHEA-synthesizing enzyme, in adult rodent CNS.