“Neuropathic pain is a neurological disorder that strongly affects the quality of life of patients. The molecular and cellular mechanisms at the basis of the neuropathic pain establishment still need to be clarified. Among the neuromodulators involved in the pathological pain pathways, endocannabinoid system could be deeply involved in both neuronal and non-neuronal mechanisms responsible for the appearance of tactile allodynia. Indeed, the function and dysfunction of this complex system in the molecular and cellular mechanisms of chronic pain induction and maintenance has been widely studied over the last two decades. In this review article, we highlighted the possible modulation of the endocannabinoid system in the neuronal, glial and microglial modulation in neuropathic pain treatment.” https://www.ncbi.nlm.nih.gov/pubmed/28237514]]>
Category Archives: Neuropathic Pain
Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometry.
“Cannabis has been used since ancient times to relieve neuropathic pain, to lower intraocular pressure, to increase appetite and finally to decrease nausea and vomiting.
The combination of the psychoactive cannabis alkaloid Δ9-tetrahydrocannabinol (THC) with the non-psychotropic alkaloids cannabidiol (CBD) and cannabinol (CBN) demonstrated a higher activity than THC alone.
Extraction efficiency of oil was significantly higher than that of water with respect to the different cannabinoids.
Fifteen minutes boiling was sufficient to achieve the highest concentrations of cannabinoids in the cannabis tea solutions.
As the first and most important aim of the different cannabis preparations is to guarantee therapeutic continuity in treated individuals, a strictly standardized preparation protocol is necessary to assure the availability of a homogeneous product of defined stability.”
https://www.ncbi.nlm.nih.gov/pubmed/28207408
Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis
“The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.” https://www.ncbi.nlm.nih.gov/pubmed/28189366]]>
The use of cannabinoids (CBs) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN): A retrospective review.
“CIPN is a common toxicity associated with the use of chemotherapy (CT) agents such as platinums, taxanes and vinca alkaloids. Patients (pts) may suffer from pain that adversely affects their quality of life, regardless of their disease trajectory.
Preclinical research has shown CBs to be effective in preventing CIPN.
CBs can be beneficial for cancer pain, although their specific benefit in pts with CIPN remains unknown.
Treatment with CBs appears to benefit some pts with CIPN.
Further research is needed to explore the optimal use of CBs in pts with CIPN.”
Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].
“Chronic pain is a complex, severe and debilitating condition which can lead to a considerable reduction in function and quality of life. Patients may present with different forms of chronic pain resulting from a number of identifiable causes, including pain due to lesion or dysfunction of the nerves, spinal cord or brain (neuropathic pain), or persistent pain caused by other non-malignant conditions, such as low-back pain or pain due to inflammation of various arthritic conditions. The prevalence of chronic non-cancer pain or neuropathic pain among Canadian adults is not well known. However, prevalence estimates using large, population-based questionnaires have shown that 4% to 8% of the general population in the developed world experiences neuropathic pain, suggesting that approximately two million Canadians may be affected by this disabling condition. Chronic pain is of particular concern among Canadians aged 65 years and older; based on cross-sectional data from the 1996/1997 National Population Health Survey and the 2005 Canadian Community Health Survey, chronic pain was estimated to affect 27% and 38% of seniors living in households and health care institutions, respectively. A number of treatments are available for the management of neuropathic pain or chronic non-cancer pain. These include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine), anticonvulsants (pregabalin, gabapentin, carbamazepine, phenytoin), topical lidocaine, and opioid analgesics. However, these medications are associated with limited pain relief and numerous adverse effects. The therapeutic use of several synthetic cannabinoid products for the symptomatic relief of chronic pain has also been studied. In particular, a combination of two products, delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) marketed under the name Sativex® is available for use as a buccal spray. This cannabis-based agent is approved for use in Canada as an add-on therapy for adult patients experiencing muscle spasticity caused by multiple sclerosis (MS), and it has received a Notice of Compliance with conditions for MS-related central neuropathic pain and the treatment of cancer pain unresponsive to opioids. The purpose of this review is to examine the available published literature relating to THC:CBD buccal spray for the treatment of chronic non-cancer or neuropathic pain in adults.”
The Role of Cannabinoid Receptors in the Descending Modulation of Pain.
“The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate.
Evidence of the involvement of cannabinoid receptors (CB) in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain.
Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord.
Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA) and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway.
Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease) and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain.
Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system diseases such as anxiety and depression.”
Activation of Cannabinoid Receptor 2 Attenuates Mechanical Allodynia and Neuroinflammatory Responses in a Chronic Post-Ischemic Pain Model of Complex Regional Pain Syndrome Type I in Rats.
“Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized.
Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes.
In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord.
Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation.
We hypothesized that CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling.
We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking).
Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord.
MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630.
Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.”
High-Intensity Swimming Exercise Decreases Glutamate-Induced Nociception by Activation of G-Protein-Coupled Receptors Inhibiting Phosphorylated Protein Kinase A.
“Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain.
Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive.
Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation.
The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice.
Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect.
Furthermore, the peripheral A1 and opioid receptors, but not CB1, are also involved in exercise’s effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase.
The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.”
A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.
“A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease.
Dose-dependent improvement in pain score was evident across all pain scale elements.
Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids.
Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.”
[Progress in study on endocannabinoids and cannabinoid receptors in the treatment for neuropathic pain].
“Endocannabinoids and cannabinoid receptors are expressed in various central pain modulation regions. They maintain in dynamic changes in the expression level and distribution under different pathological and physiological conditions. These changes possess advantage as well as disadvantage. Exogenous administration of endocannabinoids exerts analgesic effect in different pain models, which is mainly mediated by the cannabinoid CB1 and CB2 receptors. Inhibition of enzymes for degrading endocannabinoids in different pain models also shows analgesic effect due to the increased local levels of endocannabinoids.”