https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728280Both CB1 and CB2 receptors are involved in the mediation of inflammatory pain [46]. WIN-55,212-2 has been shown to attenuate the delayed phase of oro-facial pain induced by formalin injection in rats [47]. The action of WIN-55,212-2 in inflammatory pain appears to be mediated via both CB-1 and CB-2 receptors [48]. Systemic HU-308, a novel CB-2 agonist also attenuated inflammatory pain during hot plate test in mice [49]. Inflammatory pain and swelling in mouse hindepaw were relieved by systemic administration of both non-selective HU-210 and CB-2 selective JWH-133 [31], and also by local injection of CB-2 agonist AM1241 [32], [33]. Since, inflammatory pain is a hallmark of several chronic diseases including sickle cell disease and cancer, cannabinoids appear to be a promising therapy to treat severe pain in these diseases.


https://www.ncbi.nlm.nih.gov/pubmed/20304807Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1, respectively) compared with control mice expressing human hemoglobin A (HbA-BERK), indicating deep/musculoskeletal and cutaneous hyperalgesia. Peripheral nerves and blood vessels were structurally altered in BERK and hBERK1 skin, with decreased expression of mu opioid receptor and increased calcitonin gene-related peptide and substance P immunoreactivity. Activators of neuropathic and inflammatory pain (p38 mitogen-activated protein kinase, STAT3, and mitogen-activated protein kinase/extracellular signal-regulated kinase) showed increased phosphorylation, with accompanying increase in COX-2, interleukin-6, and Toll-like receptor 4 in the spinal cord of hBERK1 compared with HbA-BERK. These neurochemical changes in the periphery and spinal cord may contribute to hyperalgesia in mice expressing HbS. In BERK and hBERK1, hyperalgesia was markedly attenuated by morphine and cannabinoid receptor agonist CP 55940. We show that mice expressing HbS exhibit characteristics of pain observed in sickle cell disease patients, and neurochemical changes suggestive of nociceptor and glial activation. Importantly, cannabinoids attenuate pain in mice expressing HbS.


https://www.ncbi.nlm.nih.gov/pubmed/26703965Sickle cell anemia is a manifestation of a single point mutation in hemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life. Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice. Morphine is the common analgesic treatment but also remains a major challenge due to its side effects and ability to activate mast cells. We, therefore, examined cannabinoid receptor-specific mechanisms to mitigate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor-2-deleted sickle mice. We show that cannabinoids mitigate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice. This study provides 'proof of principle' for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anemia.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913454 Mice expressing HbS exhibited a variety of structural and neurochemical changes in the periphery and spinal cord. BERK and hBERK1 skin was less innervated, and the epidermis and dermis were thinner than in control HbA-BERK. The epidermis of MOR knockout mice is thinner than that of wild-type mice.41 Selective loss of motor and sensory nerve after neuronal injury also results in epidermal thinning.42 Therefore, down-regulation of MOR and reduction in innervation of the skin of mice expressing HbS, as observed by us, may contribute to thinning of the epidermis. A decrease in innervation is also indicative of peripheral neuropathy and suggests a neuropathic pain condition. Sprouting and perhaps regeneration of nerve fibers seen near the areas of nerve loss in BERK skin appear to be similar to those shown in neuropathic and inflammatory pain models.43 Because lymphatic vessels are involved in immune cell trafficking, stringy and distorted lymphatic vessels in hBERK1 and BERK may be dysfunctional and therefore contribute to inflammation. Further, increased expression of CGRP and SP in the skin is suggestive of neurogenic inflammation. Dilated vessels in BERK may be the result of increased CGRP, a known vasodilator. CGRP and SP are increased in persistent and inflammatory pain states.22,44 Increased release of CGRP and SP may contribute to sensitization of nociceptors and hyperalgesia.16 It appears that the inflammatory state in hBERK1 and BERK may be further compounded by proinflammatory pain mediators and neurogenic inflammation.

The transgenic mice used in the present study may be useful in identifying neural mechanisms of pain in SCD. These mice exhibit musculoskeletal and cutaneous hyperalgesia, and structural and neurochemical changes in the periphery and in the spinal cord that may contribute to sensitization of nociceptors and dorsal horn neurons. Our observations in these mice suggest that both systemically administered and locally applied cannabinoids may be beneficial in treating pain in SCD.



Cannabis -vs- Sickle Cell Anemia

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