The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function.

Chronic pain has a debilitating consequences on health and lifestyle. The currently available analgesics are often ineffective and accompanied by undesirable adverse effects. Although adenosine receptors (AR) activation can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 ARs) are not fully understood. The aim of this study was to investigate the role of different AR ligands on inflammatory pain. The von Frey filament test was used to assess the anti-nociceptive effects of adenosine ligands on Complete Freund's Adjuvant (CFA)-induced mechanical allodynia in (180-220 g) adult male Sprague Dawley rats (expressed as paw withdrawal threshold, PWT). Neither the A2AAR selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2BAR selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, the A1AR selective agonist ( ±)-5'-Chloro-5'-deoxy-ENBA, the A3AR selective agonist 2-Cl-IB-MECA, the A2AAR selective antagonist ZM 241385 and the A2BAR selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. Co-administration of the selective antagonists of A1AR and A3AR PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reversed the anti-nociceptive effects of their corresponding agonists. Furthermore, calcium imaging studies reveled that the effective AR ligands in the behavioral assay also significantly inhibit capsaicin-evoked calcium responses in cultured rat dorsal root ganglia (DRG) neurons. In conclusion, modulating the activity of the transient receptor potential vanilloid 1 (TRPV1) receptor by ARs ligands could explain their anti-nociceptive effects observed in vivo. Therefore, the cross talk between ARs and TRPV1 receptor may represent a promising targets for the treatment of inflammatory pain conditions.

Cisplatin Provokes Peripheral Nociception and Neuronal Features of Therapy-Induced Senescence and Calcium Dysregulation in Rats.

Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-ß-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.

Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague-Dawley rats (200-250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca 2+ ] i in dorsal root ganglia (DRG) neurons ex vivo . Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.

The impact of pharmacist-led educational intervention on pneumococcal vaccine awareness and acceptance among elderly in Jordan.

Limited data exist regarding pneumococcal vaccination coverage among the elderly in Middle Eastern countries including Jordan. The pharmacists' role in improving vaccine acceptance has become increasingly evident. Yet, large-scale studies of the assessment of the pharmacists' role on pneumococcal vaccines acceptance among the elderly are scarce. Hence, we assessed for the first time the current state of knowledge and pneumococcal vaccination coverage among the elderly and the role of pharmacist-led educational intervention on the attitude, awareness, vaccine acceptance, and prompts for physician consultation regarding pneumococcal vaccines in Jordan. This interventional study enrolled 916 randomly selected adults aged ≥ 65 years in Amman, Jordan. We showed that only 3.9% of the participants have ever heard about pneumococcal disease with 0.5% vaccination coverage. Immediately after educational intervention, 21.7% of the participants perceived pneumococcal disease as a threat, 52.1% of them believed in the importance of the vaccine, and 93.9% of them were willing to consult a physician in this regard. At a two-month follow-up, 30.5% had a positive attitude toward the vaccine and 36% consulted their physician regarding the vaccine. Vaccination coverage was significantly increased to 1.9% (P value = 0.008). The main obstacles against vaccination were a negative attitude and that physicians had not recommended the vaccine. Vaccine uptake was significantly associated with physician consultation (P value = 0.011). Insurance, employment, attitude, and reading the booklet significantly predicted physician consultation. In conclusion, very low pneumococcal vaccination coverage was observed among the elderly in Jordan. Enrollment of pharmacists in immunization education and recommendation is suggested to improve pneumococcal vaccine coverage among the elderly in Jordan.