The role of the blood–brain barrier in the development and treatment of migraine and other pain disorders

Abstract

The function of the blood–brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood–spinal cord barrier and blood–nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine.

The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis

“…CGRP is expressed both centrally and peripherally. Recently, the view that there is no clear proof of breakdown or leakage in the BBB during migraine attack has emerged [56–58], so macromolecular drugs may not cross the BBB. Another view is that these macromolecular drugs act mostly peripherally for prophylaxis [55, 59, 60].…”

The Role of Adenosine Signaling in Headache: A Review

“…Activation of microglia and astrocytes also modulate blood-brain barrier (BBB) permeability which has been associated with migraine patients [111,112,113,114]. Breakdown of the BBB has been hypothesized to play a key role in migraine.…”

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System

“…When administered to patients before tonsillectomy, gabapentin and diclofenac reduce post-operative opioid consumption, which may be due to the ability of these drugs to modulate P-gp transport activity at the BBB [87, 88]. We have shown that diclofenac can alter P-gp activity and morphine’s effects on nociception in rats [89]. These findings emphasize that the disease state, specific drug(s), time course, and potential drug-drug interactions in question all need to be carefully considered when developing regimens to optimize CNS drug delivery.…”