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Substance P and sickle cell disease—a marker for pain and novel therapeutic approaches

The mechanisms of pain in sickle cell disease (SCD) and its acute, recurrent, chronic, and neuropathic pain syndromes have been an enigma since their initial clinical descriptions more than a century ago. The report in this issue of the Journal by Brandow et al (2016) confirms our earlier observation of elevated plasma substance P (SP) in patients with SCD (Michaels et al, 1998). Substance P is an undecapeptide tachykinin which initiates biological effects following its interaction with its preferred receptor, Neurokinin 1, which is a G-protein coupled receptor. These findings not only suggest that plasma SP levels may be an important measure for pain in SCD, but also that a clinical trial of a neurokinin-1 receptor antagonist would be a potential therapeutic approach toward treating SCD pain. The initial observations among Africans, and the observation of SCD children who have resistance to malaria and leg ulcers, were among the earliest clinicopathological discoveries related to SCD. There have been exciting and unique developments in the studies of the biology of pain in SCD and its mechanisms, and these investigators offer new insights into its pathophysiology (Ballas et al, 2012; Brandow et al, 2015). Brandow et al (2015) undertook a systematic review of the neurobiology of pain in SCD. In murine SCD models, inhibition in three pathways involving different mechanisms reversed mechanical, cold and heat hypersensitivity. Inhibition was demonstrated by cannabinoid receptor antagonists the mast cell inhibitors cromolyn sodium and imatinib, and the mechanical pain receptors, the TRPV family of transient receptor potential cation channels. A single clinical trial of trifluoperazine, an anti-psychotic that inhibits calcium calmodulin protein kinase II alpha, was done in 18 SCD adults and this drug showed safety and decreased pain intensity (Reviewed in Brandow et al, 2015). Elevated plasma levels of SP have been implicated as a possible component in the pathophysiology of SCD (Michaels et al, 1998; Douglas, 2008). A group of patients had elevated SP levels at baseline, compared to controls and plasma SP levels were further increased during acute SCD crisis. This study included 30 well children, aged 2–18 years old with SCD, as well as 21 children with SCD in pain crisis and age-matched controls (Michaels et al, 1998). SP as well as interleukin 8 levels were increased in SCD, as compared with the control group. The plasma tumour necrosis factor (TNF) levels were similar in the groups of patients in this study. It was speculated that SP is important in pain and inflammation in SCD and may be a measurable laboratory marker of vaso-occlusive crises (Michaels et al, 1998; Douglas, 2008). Further, it was proposed that treatment with a neurokinin-1 receptor antagonist may have a therapeutic role in the treatment of SCD crisis pain (Michaels et al, 1998; Douglas, 2008). The recent paper by Brandow et al (2016) has confirmed and extended these findings. In their study, measured plasma SP levels were elevated in SCD, and these elevations correlated with haemolysis. In addition, patients taking hydroxycarbamide had increased plasma SP levels. In their provocative paper, Brandow et al (2016) raise further, important questions about the role of SP, not only as a biomarker, but also of pathophysiological significance in nociceptor sensitization leading to increased release of SP. The complex associations between plasma SP, neuropathic pain, haemolysis, and downstream pathophysiology are elegantly considered (Ballas et al, 2012). In addition, Brandow et al (2016) report the association of haemolysis with nitric oxide depletion and oxidative stress, which can in turn potentially impact peripheral and/or central nociceptor sensitization and chronic neuropathic pain in a vicious cycle. Moreover, it has recently been demonstrated that SP treatment of monocytemacrophages ex vivo favours upregulation of the CD163 surface receptor, the haemoglobin-haptoglobin receptor and leads to a proinflammatory macrophage polarization phenotype (Tuluc et al, 2014). Striking, and of significance, recent studies have demonstrated in a mouse model that mast cell activation Correpondence: Steven D. Douglas, MD, Department of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine, University of Pennsylvania, Abramson Research Center, Room 1208, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA. E-mail: douglas@email.chop.edu editorial comment