Mark A. Schumacher

This chapter reviews the scientific and clinical evidence supporting the use of topical formulations containing the pungent principle of chili peppers—capsaicin, for the treatment of peripheral neuropathic pain. Given the limitations of current oral and parenteral therapies for the management of pain arising from various forms of nerve injury, alternate therapeutic approaches that are not associated with systemic adverse events that limit quality of life, impair function, or threaten respiratory depression are critically needed. Moreover, neuropathic conditions can be complicated by progressive changes in the central and peripheral nervous system, leading to persistent reorganization of pain pathways and chronic neuropathic pain. Recent advances in the use of high-dose topical capsaicin preparations hold promise in managing a wide range of painful conditions associated with peripheral neuropathies and may in fact help reduce suffering by reversing progressive changes in the nervous system associated with chronic neuropathic pain conditions.

“What accounts for such divergent and often lackluster outcomes in the use of glucocorticoids in the treatment of back pain?…Perhaps there are additional spinal-ganglionic steroid-receptor pathways that confound the resolution of injury-induced neuroinflammation and pain.”

Background: The capsaicin receptor, transient receptor potential vanilloid type −1 (TRPV1) directs complex roles in signal transduction including the detection of noxious stimuli arising from cellular injury and inflammation. Under pathophysiologic conditions, TRPV1 mRNA and receptor protein expression are elevated in dorsal root ganglion (DRG) neurons for weeks to months and is associated with hyperalgesia. Building on our previous isolation of a promoter system for the rat TRPV1 gene, we investigated the proximal TRPV1 P2-promoter by first identifying candidate Sp1-like transcription factors bound in vivo to the P2-promoter using chromatin immunoprecipitation (ChIP) assay. We then performed deletion analysis of GC-box binding sites, and quantified promoter activity under conditions of Sp1 / Sp4 over-expression versus inhibition/knockdown. mRNA encoding Sp1, Sp4 and TRPV1 were quantified by qRT-PCR under conditions of Sp1/Sp4 over-expression or siRNA mediated knockdown in cultured DRG neurons. Results: Using ChIP analysis of DRG tissue, we demonstrated that Sp1 and Sp4 are bound to the candidate GC-box site region within the endogenous TRPV1 P2-promoter. Deletion of GC-box “a“ or “a + b” within the P2-promoter resulted in a complete loss of transcriptional activity indicating that GC-box “a“ was the critical site for promoter activation. Co-transfection of Sp1 increased P2-promoter activity in cultured DRG neurons whereas mithramycin-a, an inhibitor of Sp1-like function, dose dependently blocked NGF and Sp1-dependent promoter activity in PC12 cells. Co-transfection of siRNA directed against Sp1 or Sp4 decreased promoter activity in DRG neurons and NGF treated PC12 cells. Finally, electroporation of Sp1 or Sp4 cDNA into cultures of DRG neurons directed an increase in Sp1/Sp4 mRNA and importantly an increase in TRPV1 mRNA. Conversely, combined si-RNA directed knockdown of Sp1/Sp4 resulted in a decrease in TRPV1 mRNA. Conclusion: Based on these studies, we now propose a model of TRPV1 expression that is dependent on Sp1-like transcription factors with Sp4 playing a predominant role in activating TRPV1 RNA transcription in DRG neurons. Given that increases of TRPV1 expression have been implicated in a wide range of pathophysiologic states including persistent painful conditions, blockade of Sp1-like transcription factors represents a novel direction in therapeutic strategies.

In ancient times, physicians had a limited number of therapies to provide pain relief. Not surprisingly, plant extracts applied topically often served as the primary analgesic plan. With the discovery of the capsaicin receptor (transient receptor potential cation channel, subfamily V, member 1 [TRPV1]), the search for “new” analgesics has returned to compounds used by physicians thousands of years ago. One such compound, capsaicin, couples the paradoxical action of nociceptor activation (burning pain) with subsequent analgesia following repeat or high‐dose application. Investigating this “paradoxical” action of capsaicin has revealed several overlapping and complementary mechanisms to achieve analgesia including receptor desensitization, nociceptor dysfunction, neuropeptide depletion, and nerve terminal destruction. Moreover, the realization that TRPV1 is both sensitized and activated by endogenous products of inflammation, including bradykinin, H+, adenosine triphosphate, fatty acid derivatives, nerve growth factor, and trypsins, has renewed interest in TRPV1 as an important site of analgesia. Building on this foundation, a new series of preclinical and clinical studies targeting TRPV1 has been reported. These include trials using brief exposure to high‐dose topical capsaicin in conjunction with prior application of a local anesthetic. Clinical use of resiniferatoxin, another ancient but potent TRPV1 agonist, is also being explored as a therapy for refractory pain. The development of orally administered high‐affinity TRPV1 antagonists holds promise for pioneering a new generation of analgesics capable of blocking painful sensations at the site of inflammation and tissue injury. With the isolation of other members of the TRP channel family such as TRP cation channel, subfamily A, member 1, additional opportunities are emerging in the development of safe and effective analgesics.

The capsaicin receptor (TRPV1) is a non-selective cation channel predominantly expressed in specialized sensory neurons that detect painful stimuli. Although its many functional roles continue to be revealed, it has been confirmed to play a critical role in the perception of peripheral inflammatory hyperalgesia and pain. TRPV1 not only is sensitized and/or activated under a wide range of conditions including inflammation and nerve injury but also undergoes changes in expressed levels in response to these same pathologic conditions. Just as our understanding of the structural requirements of TRPV1 activation has grown, there is evidence that TRPV1 forms heteromeric channel complexes. This review is focused on the structural and functional consequence of TRPV1 splice variants: VR.5'sv, TRPV1b/beta and TRPV1var. Through their co-expression and formation of heteromeric complexes with TRPV1, they have been shown to modulate TRPV1 activation. Moreover, TRPV1 splice variant subunits may also contribute unique properties of activation such as the detection of hypertonic conditions.

The capsaicin receptor, also known as ‘transient receptor potential vanilloid receptor subtype 1’ (TRPV1, VR1), is an ion channel subunit expressed in primary afferent nociceptors, which plays a critical role in pain transduction and thermal hyperalgesia. Increases in nociceptor TRPV1 mRNA and protein are associated with tissue injury–inflammation. As little is understood about what controls TRPV1 RNA transcription in nociceptors, we functionally characterized the upstream portion of the rat TRPV1 gene. Two functional rTRPV1 promoter regions and their transcription initiation sites were identified. Although both promoter regions directed transcriptional activity in nerve growth factor (NGF) treated rat sensory neurons, the upstream Core promoter was the most active in cultures enriched in sensory neurons. Because NGF is a key modulator of inflammatory pain, we examined the effect of NGF on rTRPV1 transcription in PC12 cells. NGF positively regulated transcriptional activity of both rTRPV1 promoter regions in PC12 cells. We propose that the upstream regulatory region of the rTRPV1 gene is composed of a dual promoter system that is regulated by NGF. These findings support the hypothesis that NGF produced under conditions of tissue injury and/or inflammation directs an increase of TRPV1 expression in nociceptors in part through a transcription‐dependent mechanism.