Current evidence of cannabinoid‐based analgesia obtained in preclinical and human experimental settings

Lötsch, Jörn; Weyer-Menkhoff, Iris; Tegeder, Irmgard

doi:10.1002/ejp.1148

Cited by 100 publications

(67 citation statements)

References 191 publications

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“…Other studies reported the therapeutic effect of the Δ9‐tetrahydrocannabinol (THC), compound 40 , a major ingredient of Cannabis sativa , in preventing the hallmark characteristics of AD . THC is one of the most potent CB1 agonists, with an EC 50 less than 50 nM .…”

Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

182

159

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

182

159

View full text Add to dashboard Cite

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“…These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents, and activation of these receptors via endogenous GABA release contributes to the suppression of colonic afferent excitability and visceral nociception without the central nervous system [162]. The antinociceptive effects of cannabinoids were confirmed in preclinical models of inflammatory, cancer, and neuropathic pain and in several human studies [163].…”

Section: Other Inhibitory Receptorsmentioning

confidence: 72%

Peripheral Sensitization

Wei¹,

Tao²,

Yang³

et al. 2020

Peripheral Nerve Disorders and Treatment

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Peripheral sensitization indicates increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation, which usually occurs after peripheral tissue injury and inflammation. As an integral part of pain, peripheral sensitization and its mechanisms have received much attention, and numerous types of neurotransmitters and chemicals related to peripheral sensitization were investigated. We developed an animal model of peripheral sensitization, and it provides evidence that some neurotransmitters, such as glutamate and substance P, release from adjacent peripheral nerves contributing to the peripheral sensitization of pathological pain. In this chapter, we reviewed the advances in peripheral sensitization, and it will provide a basis for new targets to attenuate pain of peripheral origin.Several animal models of various pain states have been established to investigate the mechanisms of peripheral sensitization, for example, inflammation pain models, neuropathic pain evoked by disease or damage to peripheral nerves, and post-operative pain models. Animal models of inflammatory pain have used a number of different irritants that are injected into skin, paw, muscle, joint, and visceral organ. Carrageenan, complete Freund's adjuvant (CFA), and capsaicin are commonly used inflammatory irritants to induce hyperalgesia. Common nerve injury models include: (1) ligating or transecting the spinal nerves, such as spinal nerve ligation model (SNL); (2) ligating or lesioning the sciatic nerve, such as chronic constriction injury (CCI); and (3) ligating distal branches (peroneal and tibial) of the sciatic nerve (spared nerve injury) [16].To better understand the mechanisms of transmission between peripheral sensory nerve endings, we have successfully established an electrophysiological animal model in which antidromic electrical stimulation of a sensory nerve excites the adjacent primary afferents from the different spinal segments [17]. In this model, two adjacent cutaneous branches of spinal dorsal rami in the thoracic segments, T9 and T10, were dissociated and transected proximally from the spinal cord in anesthetized rats. Then antidromic electrical stimulation with 0.5 ms pulse duration, 20 Hz frequency, and 1 mA intensity was applied to T9 spinal nerve branch, and the nerve activities of T10 nerve branch were recorded [18]. All recorded afferent neurons from the T10 cutaneous branch were classified as Aβ, Aδ, and C fibers according to the conduction velocity and the receptive properties [19]. The discharges of the isolated Aβ, Aδ, and C fibers of the T10 cutaneous branch were significantly enhanced by antidromic electrical stimulation of the adjacent T9 spinal nerve branch [18]. It is in line with our previous studies that antidromic stimulation of T9 spinal nerve branch can activate and sensitize Aβ, Aδ, and C fibers obtained from the adjacent T10 dorsal cutaneous branch [20][21][22][23]. The activation and sensitization of these fibers not only occur between the peripheral sensory nerve...

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“…Actions through CB1 receptors may evoke a beneficial effect against neuropathic pain. Actions through CB2 may evoke a beneficial effect against inflammatory pain [18]. Analgesic effects of cannabinoids may also be induced by an inhibition of calcitonin release and an inhibition of a nerve growth factor.…”

Section: Analgesics Administered Topicallymentioning

confidence: 99%

Transdermal and Topical Drug Administration in the Treatment of Pain

et al. 2018

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The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.

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Current evidence of cannabinoid‐based analgesia obtained in preclinical and human experimental settings

Cited by 100 publications

References 191 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Peripheral Sensitization

Transdermal and Topical Drug Administration in the Treatment of Pain

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