Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects.

Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for PPARα and PPARγ, two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator KDM6s, in both investigated brain areas. Moreover, decreased PTEN mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior.

Neuropathic pain is a major symptom of Fabry–Anderson disease (FD). It develops in childhood, is life-lasting, and resists current therapies; finding new therapeutic strategies is urgently needed. We demonstrate that neuroinflammation control effectively relieves FD pain. We used 2 pharmacological approaches: the microglial inhibitor minocycline and the block of the activity of the chemokine prokineticin-2 with the specific receptor antagonist PC1 (patented compound 1). Ten- and 25-week-old male GLA ^−/− mice (the FD murine model) were used. These mice were characterized by mechanical allodynia, thermal hyperalgesia, hyposensitivity to cold stimuli, and abdominal pain. Two weeks of treatment with minocycline or PC1 successfully counteracted sensory alterations. A significant inflammatory state, characterized by high levels of prokineticin-2 and proinflammatory cytokines, was present in the FD gut. The sciatic nerve showed initial severe neuroinflammation that attenuated over time. In dorsal root ganglia, neuroinflammation was severe and persistent with prokineticin-2, proinflammatory cytokines, ionized calcium-binding adapter molecule 1, and glial fibrillary acidic protein overexpression; histone demethylases KDM6A and B were also upregulated. We highlighted neuroinflammation in the spinal cord that increased over time. Treatment with minocycline or PC1 significantly counteracted inflammation and neuroinflammation, reducing prokineticin-2 and proinflammatory cytokines levels and increasing anti-inflammatory factor PPARγ expression. Both treatments prevented the onset of micro- and astrogliosis in the spinal cord. We underline the role of neuroinflammation and microglia in FD pain and suggest that treatments that control the activity of the prokineticin system, glial activation, and the production of proinflammatory cytokines and increase anti-inflammatory mediators have a therapeutic effect on pain in FD.

Different drugs of abuse affect the Central Nervous System (CNS) neuronal networks and reshape the expression of neuroplasticity-related genes in crucial parts of the mesocorticolimbic reward circuitry, such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Recent evidence suggests that neuronal activity and life experience, including repeated drug exposure, can modulate oligodendrogenesis thus altering neuronal myelination. This study aimed to investigate whether the prolonged exposure to nicotine, via electronic cigarettes, affects oligodendrocyte differentiation. Results showed that exposure to nicotine mainstream enhances the expression of OLIG2, a transcription factor essential for oligodendrocyte differentiation, in male rat VTA. This effect was associated with increased mRNA levels of the epigenetic enzyme Kdm6b, which is involved in regulating OLIG2 expression and synaptic plasticity. In the same brain region, nicotine increased Bdnf and TrkB gene expression as well as dynorphin peptide levels, which are positive regulators for oligodendroglial differentiation. Noteworthy, these molecular changes occurred alongside a reduction in neurofilament light levels, suggesting potential axonal remodelling associated with enhanced oligodendrogenesis. No significant changes in investigated parameters were detected in the NAc, thus suggesting that the reported molecular alterations selectively occurred in the VTA. Protein correlation analysis revealed that prolonged nicotine exposure primarily affects neuroplasticity-related protein networks within this area. Overall, these findings suggest that prolonged nicotine exposure, through electronic cigarettes, induces alterations of oligodendrogenesis modulators in the VTA. These molecular changes may impact axonal conduction velocity and reward circuitry connectivity, promoting neuronal adaptations that could be relevant for the development of addictive behaviour.

Early-life exposure to environmental stressors may increase the risk of disease later in life. Chlorpyrifos (CPF), a widely used pesticide and acetylcholinesterase inhibitor, can cross the placental barrier and can be found in breast milk, leading to excessive cholinergic stimulation. Acetylcholine is involved in sleep and respiratory regulation. The main objective of this study was to investigate whether perinatal CPF exposure affects sleep-related breathing together with promotion of neuroinflammatory processes in adulthood. To explore these effects, CPF (5 mg/kg/day) or vehicle was administered orally to dams from mating to weaning. The offspring were not directly treated. At 17–18 weeks of age, male and female offspring underwent electroencephalographic and electromyographic electrode implantation to monitor sleep-wake cycles. Recordings were conducted over 48 hours in home cages, and for 7 hours in a plethysmographic chamber to assess sleep-related breathing pattern. At the end of recordings, hippocampal tissues were collected for gene expression analysis via real-time PCR. Results revealed that CPF perinatal exposure increased sighs and apneas during sleep in adult mice, especially in female. Additionally, expression of pro-inflammatory cytokines was upregulated while expression of peroxisome proliferator-activated receptor genes was downregulated in the hippocampus of female mice born to CPF-treated dams. These findings suggest that perinatal CPF exposure can induce long-lasting alterations in sleep-related respiratory patterns and hippocampal inflammatory responses, with a sex-specific susceptibility—females being more affected. This highlights the perinatal period as a critical window of vulnerability to environmental toxicants such as pesticides. The results support the hypothesis that adult sleep and brain inflammation phenotypes may be modulated by early-life chemical exposures during pregnancy and lactation.