An Evolving Concept: The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment
Chronic pain is a serious healthcare dilemma with many treatment options available, such as antidepressants, non-steroidal anti-inflammatory drugs, opioids, and anticonvulsants; nevertheless, chronic pain presently is not appropriately managed.
A fundamental reason for the lack of effective treatment is that none of these drugs specifically target a process that is essential in eliciting a mechanism fundamental in the etiology of chronic pain pathology. Yet, prescriptions for these drugs, and in particular opioids, are increasingly provided to patients. As a consequence, a recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioids for misguided treatment purposes, because opioids rarely relieve chronic pain fully, may contribute to worsening of pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, and potential for addiction and overdose deaths exist. Accordingly, there is an urgent need for an alternative, non-opiate treatment of chronic pain.
Chronic pain is based on a mental perception with a cognitive feature and occurs subsequent to the development of neuroplastic changes at higher centers of the brain. With this understanding, we have investigated how a pro-inflammatory cytokine known to be proximally involved in one of the major causes of chronic pain, injury at a peripheral site, and in the development of the inflammatory loci, could at the same time have a fundamental function at higher centers of the brain by simultaneously being involved in neuron functioning.
An extensive understanding of the involvement of a pro-inflammatory cytokine on neuron functioning in the brain may well define and thus elucidate the neuroplastic changes that are integral in the etiology of chronic pain. In fact, the pleiotropic and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNFα), known to orchestrate the cellular reactions in an inflammatory lesion, has been shown to affect not only pathological and inflammatory conditions, but also neurological disorders, and it participates in a seminal role in the maintenance of physiological homeostasis.
Due to these diverse activities, TNFα has been and still is widely investigated. Preclinical studies from our laboratory and others show that heightened levels of TNFα in the brain are both sufficient as well as necessary for the development of chronic pain behaviors, such as hyperalgesia and allodynia [1-5]. It is therefore apparent that by regulating either the expression of or the response to TNFα selectively in the brain, a robust effect would be envisaged on the onset, development and maintenance of chronic pain.
With the goal of testing this hypothesis, we are discovering that drugs that selectively lower TNFα levels and their method of delivery that solely affect levels only in the brain are effective as treatment paradigms in chronic pain animal models. For example, total relief of peripheral hypersensitivity in neuropathic pain models (chronic constriction injury and spared nerve injury) was achieved through the specific blockade of brain TNFα following either direct intracerebroventricular or intracerebral injection [1,3,6].
However, due to the invasiveness of these procedures (requiring drilling of burr holes in the skull and/or inserting needles into the parenchyma of the brain) to achieve brain delivery, the present challenge is to explore novel, peripheral, non-invasive methods for the selective inhibition of TNFα solely in the brain for clinical application. Yet, it is difficult to direct anti-TNFα agents to the brain by peripheral administration, because clinically available TNFα blockers (i.e., etanercept, Infliximab) are large molecules that do not easily enter the brain via standard administration (intravenous, per os) protocols. Only negligible quantities of these biologic agents reach the brain when delivered by standard peripheral routes and therefore have little effect on this organ. Intrathecal injection is often employed in the clinical setting to deliver agents to the cerebrospinal fluid. However, this method of delivery is both invasive, requiring penetration of the ligamentum flavum and the dura using a long spinal needle, and limited with only partial distribution to the ventricles, and with the remainder of the injection having alternate peripheral distribution.
Thus, it is apparent that therapy for the many neurological disorders requires a more direct and non-invasive route for drug delivery/access to the brain. We are currently investigating and establishing the perispinal route of delivery, which completely offers this access [7-9]. The delivery consists of a non-invasive peripheral perispinal injection in the posterior neck region (into the posterior spinal venous plexus), which permits direct drug access to the ventricles of the brain via the choroid plexus following Trendelenburg positioning. The enhanced hydrostatic pressure during Trendelenburg positioning forces a compound through a valve-less system contiguous with the cerebrospinal venous system and into the ventricles. Once in the ventricles, the biologics can intimately communicate with the brain parenchyma.
This therapeutic method is distinct from intrathecal (or epidural) injection, as there is no risk of needle injury to the spinal cord or to the epidural veins since perispinal administration is external to the ligamentum flavum. Targeting TNFα (i.e., decreasing activity) in the brain, as opposed to activating the opioid pathway or other nonspecific mechanism, provides a superior novel pain target that is potent and ready for clinical translation to benefit patients with chronic, treatment-resistant pain. Based on our experience using this pioneering breakthrough in the clinical setting, we are confident that this technology provides a safe, non-addictive treatment of analgesia, with greater efficacy than current treatments [10,11].
Based on our many years of research along with extensive literature by other investigators, we propose that the directed delivery of drugs that solely dampen TNFα levels in the brain establishes an analgesic mechanism of action necessary for a pioneering breakthrough of novel drugs that are efficacious for treating chronic pain. Not only would this treat chronic pain, but it would also avoid the myriad side-effects associated with treatment options presently available, effects that prevent their possible true potential. In fact, we also propose that the therapeutic efficacy endowed by compounds such as tricyclic antidepressant drugs is because of their ability to reestablish homeostatic TNFα concentrations within the brain; we have identified the mechanism of decreasing TNFα levels in the brain elicited by tricyclic antidepressant drugs that explains the analgesic property of these drugs and which may be harnessed for effective treatment of chronic pain [12,13]. However, because of their ancillary unwarranted side-effects their use is tentative at best.
In conclusion, our research has shown that by either blocking pathologic TNFα activity or decreasing TNFα production solely in the brain (avoiding peripheral distribution) has profound patient benefits. This profound effect on chronic pain pathology is mediated through the reduction of the associated role of TNFα as a neuromodulator in addition to its role of orchestrating inflammation. Excess levels of a proximal pro-inflammatory cytokine are usually abnormal, and the administration of specific anti-TNFα compounds can reduce or arrest this inflammatory and aberrant neuromodulatory response effectively. Subsequent to an insult, such as traumatic brain injury, stroke, concussion, or peripheral injury, the disruption of brain-TNFα homeostasis generates maladaptive alterations which produce chronic pain. Achieving reduced inflammation in the brain after succumbing to an insult can restore appropriate brain functions. At such a time, viable tissue remains in a dysfunctional state due to abnormal, unnecessary levels of TNFα. Therefore, it is expected that administration of anti-TNFα biologics via perispinal injection achieves a very efficient decrease in TNFα expression throughout the brain parenchyma.
Robert N. Spengler, Ph.D.b and Tracey A. Ignatowski, Ph.D.a,b – aDepartment of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14203 bNanoAxis, LLC, Clarence, New York 14031
- Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFα mediates neuropathic pain. Brain Res, 1999; 841: 70-77.
- Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFα: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res, 2000; 859: 113-122.
- Gerard E, Spengler RN, Bonoiu AC, Davidson BA, Mahajan SD, Ding H, Kumar R, Prasad PN, Knight PR, Ignatowski TA. Chronic pain is relieved by nanomedicine-mediated decrease of hippocampal TNF. PAIN, 2015; 156: 1320-1333.
- Martuscello RT, Spengler RN, Bonoiu AC, Davidson B, Helinski J, Ding H, Mahajan S, Kumar R, Bergey EJ, Knight PR, Prasad PN, Ignatowski TA. Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. PAIN, 2012; 153: 1871-1882.
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- Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs, 2014; 28(8): 679-697.
- Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clin Drug Investig, 2014; 34(5): 361-366.
- Ignatowski TA, Reynolds JL, Sud R, Knight PR, Spengler RN. The dissipation of neuropathic pain paradoxically involves the presence of tumor necrosis factor-α (TNF). Neuropharmacology, 2005; 48: 448-460.
- Sud R, Spengler RN, Nader ND, Ignatowski TA. Antinociception occurs with a reversal in α2- adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory. Eur J Pharmacol, 2008; 588: 217-231.
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