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Persistent opioid use following total joint replacement (TJR) surgery is common; however, the association between pre-surgical opioid use and surgery type has not been established. The objective of this study was to determine the association between pre-surgery opioid use and persistent post-surgery opioid use in TJR patients compared to other elective surgical patients.
Learn More >A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area), has been proposed as an inhibitory control center for dopaminergic activity of the ventral tegmental area (VTA). This region is composed of GABAergic cells which send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in-vivo, ex-vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects, and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in-vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally-infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. Additionally, chemo-activation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated-pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.
Learn More >There is an unmet medical need for non-opioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect effect PK/PD model was developed to describe the relationship between the plasma PK of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC value. Evaluation of SPR inhibition and mechanical allodynia was assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon QD p.o. administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC throughout the dose intervals leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls. SIGNIFICANCE STATEMENT: N/A.
Learn More >Cisplatin and other widely employed platinum-based anticancer agents produce chemotherapy-induced peripheral neuropathy (CIPN) that often results in pain and hyperalgesia that are difficult to manage. We investigated the efficacy of a novel bivalent ligand, MCC22, for the treatment of pain arising from CIPN. MCC22 consists of mu opioid receptor (MOR) agonist and chemokine receptor 5 (CCR5) antagonist pharmacophores connected through a 22-atom spacer and was designed to target a putative MOR-CCR5 heteromer localized in pain processing areas. Mice received once daily intraperitoneal (i.p.) injections of cisplatin (1 mg/kg) for seven days and behavior testing began 7 days later. Cisplatin produced mechanical hyperalgesia that was decreased dose-dependently by MCC22 given by intrathecal (ED = 0.004 pmol) or i.p. (3.07 mg/kg) routes. The decrease in hyperalgesia was associated with decreased inflammatory response by microglia in the spinal cord. Unlike morphine, MCC22 given daily for nine days did not exhibit tolerance to its analgesic effect and its characteristic antihyperalgesic activity was fully retained in morphine-tolerant mice. Furthermore, MCC22 did not alter motor function and did not exhibit rewarding properties. Given the exceptional potency of MCC22 without tolerance or reward, MCC22 has the potential to vastly improve management of chronic pain due to CIPN.
Learn More >The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes all marked by unilateral headache and ipsilateral cranial autonomic features. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and hemicrania continua. Pathophysiology includes the trigeminal pain system, autonomic system, hypothalamus, and more recently an identified role for the vagus nerve. Diagnosis is made after looking at headache frequency, duration, and accompanying symptoms. Each TAC has its own unique treatment, which is discussed in depth.
Learn More >Sickle cell disease (SCD) is one of the most common severe genetic diseases around the world. A majority of SCD patients experience intense pain, leading to hospitalization, and poor quality of life. Opioids form the bedrock of pain management, but their long-term use is associated with severe side effects including hyperalgesia, tolerance and addiction. Recently, excellent research has shown some new potential mechanisms that underlie SCD-associated pain. This review focused on how transient receptor potential vanilloid 1, endothelin-1/ endothelin type A receptor, and cannabinoid receptors contributed to the pathophysiology of SCD-associated pain. Understanding these mechanisms may open a new avenue in managing SCD-associated pain and improving quality of life for SCD patients.
Learn More >Individuals with migraine exhibit heightened sensitivity to visual input that continues beyond their migraine episodes. However, the contribution of color to visual sensitivity, and how it relates to neural activity, has largely been unexplored in these individuals.
Learn More >Children of parents with chronic pain have higher rates of pain and internalizing (e.g., anxiety, depressive) symptoms than children of parents without chronic pain. Parental modeling of pain behaviour and reinforcement of child pain have been hypothesized to underlie these relationships. These mechanisms were tested in a sample of 72 parents with chronic pain and their children (ages 8-15). Standardized measures were completed by parents (pain characteristics, pain interference, child internalizing) and children (pain catastrophizing, pain over previous three months, and internalizing). In a laboratory session, children completed the cold pressor task (CPT) in the presence of their parent, and parent-child verbalizations were coded. Significant indirect effects of parental pain interference on child self-reported (B = 0.12, 95% CI: 0.01, 0.29) and parent-reported (B = 0.16, 95% CI: 0.03, 0.40) internalizing symptoms through child pain catastrophizing were found (parental modeling mechanism), and were not moderated by child chronic pain status. Significant indirect effects were found between parent pain-attending verbalizations and child self-reported (B = 2.58, 95% CI: 1.03, 5.31) and parent-reported (B = 2.18, 95% CI: 0.93, 4.27) CPT pain intensity and tolerance (B = -1.02, 95% CI: -1.92, -0.42) through child pain-attending verbalizations (parental reinforcement mechanism). While further understanding of the temporal relationships between these variables is needed, the current study identifies constructs (e.g., parent pain interference, child pain catastrophizing, parent reinforcement of child pain) which should be further examined as potential targets for prevention and intervention of pain and internalizing symptoms in children of parents with chronic pain.
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