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Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.
Learn More >Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405.
Learn More >Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP.
Learn More >Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Na). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Na. Na are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Na potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.
Learn More >Although depression and chronic pain often coexist, few studies have examined antidepressant use among people with pain. This study examines the prevalence and characteristics associated with antidepressant use among people prescribed opioids for chronic noncancer pain (CNCP).
Learn More >Alcohol use and chronic pain are highly comorbid. Acute alcohol use typically produces an analgesic effect. However, chronic use can worsen the progression of chronic pain. In rodent models, acute models of pain have primarily been used to investigate the relationship between alcohol and pain analgesia. Here, we use two models of chronic pain, chronic inflammatory and peripheral neuropathic pain, to investigate acute alcohol's antinociceptive and analgesic properties. We hypothesize that acute ethanol is acting through opioid receptors to create an analgesic-like effect in both reflexive and affective dimensions of pain. Using male and female C57BL/6J mice, oral ethanol administration (0-1.25 g/kg) showed a dose-dependent reversal of mechanical hypersensitivity in both Complete Freund's Adjuvant (CFA) and chronic constriction injury (CCI) models of chronic inflammatory and neuropathic pain. No sex differences were observed. Using the conditioned place preference (CPP) task to assess the subjective responses to ethanol's anti-nociceptive properties, CCI-injured animals showed a preference for the ethanol-paired side, suggesting a reduction in an aversive and pain-like state produced by nerve injury. These effects are likely mediated through the kappa and possibly the mu opioid systems, since ethanol-induced anti-nociception following CCI was fully reversed by pretreatment with the kappa selective antagonist, nor-BNI, or high doses of naltrexone. These data show that ethanol possesses analgesic-like properties in chronic inflammatory and neuropathic pain models in mice and provide new insight into ethanol as it relates to chronic pain.
Learn More >Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine.
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