Browse by Audience
Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aβ mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.
Learn More >Clinical studies have shown that schizophrenia is accompanied by hypoalgesia. Accordingly, we have previously reported that a chronic schizophrenia-related rat substrain (Wisket) showed decreased acute heat pain sensitivity. The aim of the present study was to determine the mechanical pain sensitivity and the effects of opioid ligands in a chronic osteoarthritic pain model generated using Wisket rats. Our previous molecular biological studies indicated that the impairment in opioid and cannabinoid receptor functions observed in these animals did not explain their altered pain sensitivity. Therefore, we aimed to investigate another endogenous antinociceptive system, i.e., the oxytocinergic system (which is also implicated in schizophrenia) via the determination the brain-region specific oxytocin receptor mRNA expression in Wisket rats. Osteoarthritis was induced in male adult control Wistar rats without any interventions and in Wisket rats after juvenile social isolation and ketamine treatment. The degree of allodynia and the effects of systemic morphine or intrathecal endomorphin-1 administration were determined. Furthermore, the expression of the oxytocin receptor mRNA was assessed in different brain structures (prefrontal cortex, striatum, diencephalon, brainstem, and olfactory bulb). A lower degree of allodynia was observed in the Wisket group compared with control animals 1 and 2 weeks after the induction of osteoarthritis, which was accompanied by a comparable degree of edema. Systemically or intrathecally applied opioids caused similar time-response curves in both groups, with apparently shorter effects in Wisket animals. The expression of the oxytocin receptor mRNA was lower in most of the brain regions (with the exception of the diencephalon) investigated in Wisket rats vs. the control animals. In summary, both acute and chronic hypoalgesia (as nonspecific symptoms in patients with schizophrenia) can be simulated in Wisket animals as endophenotypes despite the impairment of the endogenous antinociceptive systems evaluated. Thus, this model might be an appropriate tool for further investigation of the molecular basis of altered pain perception in schizophrenia.
Learn More >Nerve injury-induced pain is difficult to treat. In this study, we developed an alginate scaffold with human umbilical cord mesenchymal stem cell exosomes (EX-SC) to treat nerve injury-induced pain.
Learn More >Canine neuropathic pain (NeuP) has been poorly investigated. This study aimed to evaluate the pain burden, sensory profile and inflammatory cytokines in dogs with naturally-occurring NeuP. Twenty-nine client-owned dogs with NeuP were included in a prospective, partially masked, randomized crossover clinical trial, and treated with gabapentin/placebo/gabapentin-meloxicam or gabapentin-meloxicam/placebo/gabapentin (each treatment block of 7 days; total 21 days). Pain scores, mechanical (MNT) and electrical (ENT) nociceptive thresholds and descending noxious inhibitory controls (DNIC) were assessed at baseline, days 7, 14, and 21. DNIC was evaluated using ΔMNT (after-before conditioning stimulus). Positive or negative ΔMNT corresponded to inhibitory or facilitatory pain profiles, respectively. Pain scores were recorded using the Client Specific Outcome Measures (CSOM), Canine Brief Pain Inventory (CBPI), and short-form Glasgow Composite Measure Pain Scale (CMPS-SF). Data from baseline were compared to those of sixteen healthy controls. ΔMNT, but not MNT and ENT, was significantly larger in controls (2.3 ± 0.9 N) than in NeuP (-0.2 ± 0.7 N). The percentage of dogs with facilitatory sensory profile was similar at baseline and after placebo (61.5-63%), and between controls and after gabapentin (33.3-34.6%). The CBPI scores were significantly different between gabapentin (CBPI pain and CBPI overall impression) and/or gabapentin-meloxicam (CBPI pain and interference) when compared with baseline, but not placebo. The CBPI scores were not significantly different between placebo and baseline. The concentration of cytokines was not different between groups or treatments. Dogs with NeuP have deficient inhibitory pain mechanisms. Pain burden was reduced after gabapentin and/or gabapentin-meloxicam when compared with baseline using CBPI and CMPS-SF scores. However, these scores were not superior than placebo, nor placebo was superior to baseline evaluations. A caregiver placebo effect may have biased the results.
Learn More >Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent, painful side effect which arises due to a number of chemotherapy agents. CIPN can have a prolonged effect on quality of life. Chemotherapy treatment is often reduced or stopped altogether because of the severe pain. Currently, there are no FDA-approved treatments for CIPN partially due to its complex pathogenesis in multiple pathways involving a variety of channels, specifically, voltage-gated ion channels. One aspect of neuropathic pain is hyperexcitability in dorsal root ganglia (DRG) peripheral sensory neurons. Our study employs bifurcation theory to investigate the role of voltage-gated ion channels in inducing hyperexcitability as a consequence of spontaneous firing due to the common chemotherapy agent paclitaxel. Our mathematical investigation of a reductionist DRG neuron model comprised of sodium channel Na1.7, sodium channel Na1.8, delayed rectifier potassium channel, A-type transient potassium channel, and a leak channel suggests that Na1.8 and delayed rectifier potassium channel conductances are critical for hyperexcitability of small DRG neurons. Introducing paclitaxel into the model, our bifurcation analysis predicts that hyperexcitability is highest for a medium dose of paclitaxel, which is supported by multi-electrode array (MEA) recordings. Furthermore, our findings using MEA reveal that Na1.8 blocker A-803467 and delayed rectifier potassium enhancer L-alpha-phosphatidyl-D-myo-inositol 4,5-diphosphate, dioctanoyl (PIP) can reduce paclitaxel-induced hyperexcitability of DRG neurons. Our approach can be readily extended and used to investigate various other contributors of hyperexcitability in CIPN.
Learn More >Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, and . PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens. PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD.
Learn More >Legalization of cannabis encourages the development of specific cultivars to treat disease such as neuropathic pain. Because of the large number of cultivars, it is necessary to prioritize extracts before proceeding to clinical trials.
Learn More >Neuropathic pain is among the most debilitating forms of chronic pain. Studies have suggested that chronic pain pathogenesis involves neuroimmune interactions and blood-spinal cord barrier (BSCB) disruption. However, the underlying mechanisms are poorly understood. We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. We detected CXCR3 expression in spinal neurons and observed that CCI induced CXCL10/CXCR3 activation, BSCB disruption, and mechanical hyperalgesia. CCI-induced BSCB disruption enabled circulating T cells to migrate into the spinal parenchyma. Intrathecal administration of an anti-CXCL10 antibody not only attenuated CCI-induced hyperalgesia, but also reduced BSCB permeability, suggesting that CXCL10 acts as a key regulator of BSCB integrity. Moreover, T cell migration may play a critical role in the neuroimmune interactions involved in the pathogenesis of CCI-induced neuropathic pain. Our results highlight CXCL10 as a new potential drug target for the treatment of nerve injury-induced neuropathic pain.
Learn More >Sickle cell disease is a hemoglobinopathy that causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. The development and treatment of pain, in particular, neuropathic pain in sickle cell disease patients is poorly understood and impedes our progress toward the development of novel therapies to treat pain associated with sickle cell disease. The orexin/hypocretin system offers a novel approach to treat chronic pain and hyperalgesia. These neuropeptides are synthesized in three regions: perifornical area (PFA), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH). Data suggest that orexin-A neuropeptide has an analgesic effect on inflammatory pain and may affect mechanisms underlying the maintenance of neuropathic pain. The purpose of this study was to determine whether there are neuronal activation differences in the orexin system as a result of neuropathic pain testing in a mouse model of sickle cell disease. Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS-BERK) and age-/gender-matched controls (HbAA-BERK mice; = 10/group, 20-30 g) expressing normal human hemoglobin A were habituated to each test protocol and environment before collecting baseline measurements and testing. Four measures were used to assess pain-related behaviors: thermal/heat hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and deep-tissue hyperalgesia. Hypothalamic brain sections from HbAA-BERK and HbSS-BERK mice were processed to visualize orexin and c-Fos immunoreactivity and quantified. The percentage of double labeled neurons in the PFA was significantly higher than the percentage of double labeled neurons in the LH orexin field of HbAA-BERK mice ( < 0.05). The percentages of double labeled neurons in PFA and DMH orexin fields are significantly higher than those neurons in the LH of HbSS-BERK mice ( < 0.05). These data suggest that DMH orexin neurons were preferentially recruited during neuropathic pain testing and a more diverse distribution of orexin neurons may be required to produce analgesia in response to pain in the HbSS-BERK mice. Identifying specific orexin neuronal populations that are integral in neuropathic pain processing will allow us to elucidate mechanisms that provide a more selective, targeted approach in treating of neuropathic pain in sickle cell disease.
Learn More >