Migraine

Migraine is a complex episodic neurological disorder characterized by recurrent headaches, which may be accompanied by nausea, vomiting, and sensitivity to light and sound.⁸⁶ Visual aura is also experienced in approximately 30% of all migraine episodes, and migraines are three times more prevalent in females compared to males. Currently, there is no cure for migraine headaches. Conventional medical treatment consists of non-steroidal anti-inflammatory drugs (NSAIDs), triptans, anti-epileptics, beta-blockers, and calcium channel blockers, all of which vary in efficacy with significant side effects.⁸⁷

The exact pathophysiology of migraine is not exactly known. There seems to be a hereditary component, as high as 50%. Most research points to the activation and sensitization of neurons in the trigeminal nerve as the trigger to migraine headaches. There are two possible theories as to how the nerve is aggravated—cortical spreading depression (CSD) and neurogenic inflammation. Cortical spreading depression is a wave of neural excitation activity followed by the depolarization of neurons. This may explain the aura some patients experience before the migraine episode. Neurogenic inflammation theory proposes that inflammatory neuropeptides lead to vasodilation and mast cell degranulation, followed by a release of various inflammatory compounds.⁸⁷

Adult MSCs may help combat migraine due to their immunomodulatory effects. Studies using SVF have demonstrated efficacy in the treatment of trigeminal neuropathic pain. The activation of mast cells (which are derived from hematopoietic stem cells) triggers the release of inflammatory cytokines which result in many nervous system disorders, such as migraine.⁸⁸ Additionally, pericytes play a crucial role in neurological diseases. Used correctly, they may be used to increase blood flow, preserve blood-brain barrier function, and help repair glial scarring in areas of the central nervous system (CNS).⁸⁹ Moreover, MSCs studies have demonstrated that they are neuroprotective on dopaminergic neurons.⁹⁰

There are only two published studies utilizing cells for the treatment of migraine. Bright et al. treated four females w'ith long histories of migraine or tension-type headache systemically with autologous stromal vascular fraction isolated from lipoaspirate. Two of the four women ceased having migraines after 1 month; this lasted for a period of 12 to 18 months. A third patient had a significant reduction in the severity and frequency of migraine over 18 months. The fourth patient obtained a temporary decrease in symptoms for 1 month and was treated 18 months later. Most importantly, the dosage and types of pain medication were reduced in all patients.⁹¹

Mauksop and Rothaus investigated the intra-muscular injection of SVF in nine patients with severe migraine-related disability who failed botulinum toxin injections and three prophylactic drugs. The Migraine Disability Assessment Score (MIDAS) was used to assess the patients. Patients received injections in the pericranial, neck, and trapezius muscles and were evaluated at baseline and 3 months post-treatment. The mean MIDAS score decreased 34 points. Seven out of nine patients reported a decreased MIDAS score but only two experienced meaningful improvement.⁹²

While these studies hold some promise for migraine treatment, the role of stem cells for migraines needs more research. Moreover, more studies with larger subject groups need to be completed to better evaluate the efficacy of stem cells for the treatment of migraine.

Opioid Tolerance and Opioid-Induced Hyperalgesia

Two of the most troublesome side effects of opioid use/abuse are the occurrence of opioid tolerance and opioid-induced hyperalgesia. Opioid tolerance occurs when an individual requires greater amounts of opioids over time to obtain the original degree of therapeutic effect. This does not necessarily involve addiction. Increased dosages however, can lead to overdose and death. Opioid- induced hyperalgesia describes a situation in which individuals taking opioids to treat pain paradoxically develop an increased sensitivity to noxious stimuli.⁹³ Currently, there are very few options in treating opioid tolerance or opioid-induced hyperalgesia other than medication rotation.

Molecular pathways and mechanisms tied to neuroinflammation appear to play similar, yet distinct roles in the development of both opioid tolerance and opioid-induced hyperalgesia. Opioids activate toll-like receptors on microglia, which leads to opioid tolerance. Opioid-induced hyperalgesia is mediated via p-receptor dependent expression of P2X4 and the release of brain-derived neurotropic factor (BDNF) from microglia.⁹³ This pathway regulates microglia-to-neuron signaling, leading to the sensitization of spinal lamina I neurons and opioid-induced hyperalgesia. This suggests that mediating neuroinflammation would prove beneficial in treating opioid tolerance and opioid-induced hyperalgesia.

MSCs offer hope in the treatment of opioid tolerance and opioid-induced hyperalgesia, due mostly to their paracrine effects, mainly their immunomodulatory and anti-inflammatory effects. More specifically, MSCs impede opioid tolerance and opioid-induced hyperalgesia by hindering neuroinflammation. Repetitive opioid intake activates microglia and astrocytes in the spinal cord, as well as satellite cells in the dorsal root ganglion. Opioids also directly stimulate toll-like receptors (TLR-4), resulting in the manifestation of opioid tolerance. Additionally, opioids cause mu-opioid receptor (MOR)-mediated expression of punergic receptors P2X4R and the release of BDNF from microglia. Opioid-induced hyperalgesia occurs due to the sensitization of lamina I neurons modulated by microglia-to-neuron signaling via the P2X4-BDNF-TrkB pathway.

MSCs may prevent neuroinflammation by paracrine release of a number of exosomes, microvesicles, and growth factors including indoleamine 2,3-dioxygenase (IDO), prostaglandin-2 (PGE- 2), IL-10, TGF-(3. leukemia inhibiting factor (LIF), human leukocyte antigen-G5 (HLA-G5), and TSG-6. MSCs communicate with microglia, astrocytes, macrophages, and other immune cells via various signaling pathways to discourage the manufacture and release of interleukin-l-beta, IL-6, TNF-a, BDNF, NO, and other pro-inflammatory bioactives that contribute to the development of opioid tolerance and opioid-induced hyperalgesia.⁹⁴ Additionally, MSCs release growth factors that promote cell and tissue recovery via resident stem/progenitor cell stimulation, extracellular matrix remodeling, angiogenesis, and immune function modulation.⁹⁵

Preclinical studies show promising results using MSCs to reverse opioid tolerance and opioid- induced hyperalgesia. Researchers at the Cleveland Clinic⁹³ conducted preclinical studies in rodents using MSCs harvested from rat bone marrow. Opioid tolerance was induced in rats using daily morphine injections for 3 to 4 weeks. MSCs were delivered by either intravenous or intrathecal administration 1 or 7 days before the administration of morphine to an opioid or control group. Outcome measures included paw withdrawal thresholds (PWT) to mechanical and thermal stimuli and tail flick tests. Intrathecal and intravenous MSCs did not cause any behavioral change in the control group. Both a single dose of intravenous or intrathecal administration in the opioid tolerance group significantly mitigated opioid tolerance for up to 26 days, regardless of the day of administration. The therapeutic effect took place as quickly as 2 days after treatment. In terms of opioid-induced hyperalgesia, both intravenous and intrathecal administration of MSCs produced similar degrees of anti-tolerance and anti-hyperalgesia effects. This is significant because intravenous injection is a much more easily tolerated route of administration with less risk. Immunohistochemistry illustrated that the treatments significantly reduced microglia and astrocyte activation in the spinal cord. These findings are significant as both opioid tolerance and opioid-induced hyperalgesia are the leading causes of overdose and death when increasing doses are necessary for pain relief. Human studies are currently under development to substantiate the preclinical findings. If successful, this will radically change the treatment approach to pain management.

In summary, MSCs may be promising for opioid tolerance and opioid-induced hyperalgesia assuming their main mechanisms of action are via paracrine effects. Indeed, preclinical data have illustrated a beneficial effect in animal models of addiction. More research and clinical work are needed to determine the efficacy of MSCs for opioid tolerance and opioid-induced hyperalgesia.