Novel therapeutics in the field of capsaicin and pain

Abstract

Capsaicin, a pharmacologically active agent found in chili peppers, causes burning and itching sensation due to binding at the transient receptor potential vanilloid-1 (TRPV-1) receptor, a polymodal receptor critical to the sensing of a variety of stimuli (e.g., noxious heat, bidirectional pH), and subsequent activation of polymodal C and A-δ nociceptive fibers. Acutely, TRPV-1 activation with peripheral capsaicin produces pronociceptive effects, which extends to the development of hyperalgesia and allodynia. However, capsaicin has been reported to display antinociceptive properties as well, largely through TRPV-1-dependent mechanisms. Local application of high concentration of capsaicin is used for neuropathic pain and repeated stimulation of TRPV-1 induced an improvement of epigastric pain in irritable bowel syndrome and dyspepsia patients by desensitization of nociceptive pathways. New TRPV-1 agonists are currently under preclinical study and TRPV-1 antagonists are in early clinical development as analgesics. The TRPV-1 pathway might be a novel target for therapeutics in pain sensitivity.

Keywords:

• capsaicin
• chili peppers
• functional gastrointestinal disorders
• pain
• TRPV-1

Capsaicin, the pungent alkaloid of red pepper (Capsicum annuum), has been extensively studied for its biological effects that are of pharmacological relevance [1]. These include cardio-protection, anti-lithogenic effect, anti-inflammatory and analgesia, thermogenic effect and beneficial effects on gastrointestinal system [1]. Therefore, capsaicinoids may have the potential clinical value for pain relief and weight loss. It is well known that capsaicin is a selective neurotoxin for sensory nerves, and this has led to the exploration of the functional role of these neurons, for example, at the gastrointestinal level, and to the hypothesis of dual ‘sensory-efferent’ functions mediated by capsaicin-sensitive neurons [1,2]. Capsaicin affects the afferent neurons by two distinct phases: an initial excitation followed by a long-lasting refractory state during which the neurons are not responsive to the neurotoxin and other stimuli. The refractory state (also called desensitization) is usually reversible in terms of weeks, but the systemic administration of high doses of the neurotoxin causes permanent neurotoxicity [1]. These neurons are important to transmit sensory information toward the central nervous system but also to release their neurotransmitters toward the periphery, playing a local effector role in several regulatory processes. Recent studies have shown that capsaicin specifically targets these afferent nerves via transient receptor potential vanilloid-1 (TRPV-1), a nonselective cation channel with high permeability for Ca⁺⁺ [2,3]. TRPV-1 belongs to a family of store operated Ca⁺⁺ channels and acts as a polymodal detector of potentially harmful stimuli, including capsaicin, resiniferatoxin, noxious heat, H⁺ ions, anandamide and several lipoxygenase products. Gingerol, piperine and zingerone are other spices that act as TRPV-1 agonists. Resiniferatoxin is a naturally occurring, ultrapotent capsaicin analog that activates TRPV-1in a subpopulation of primary afferent sensory neurons involved in nociception. Resiniferatoxin causes an ion channel in the plasma membrane of sensory neurons to become permeable to cations, particularly the calcium cation [3]; this evokes a powerful irritant effect followed by desensitization and analgesia. To study compounds less pungent than capsaicin, a group of analogs named capsinoids (the natural capsiate, dihydrocapsiate, and the synthetic capsiate analog vanillyl nonanoate) with similar chemical structure of lead compound and TRPV-1 agonistic properties were recently developed [4]. Confirming their analogy with capsaicin, both capsiate and its analog vanillyl nonanoate protected rat gastric mucosa from ethanol-induced injury, and this effect was reverted by prior administration of the TRPV-1 antagonist capsazepine [4]. Rutaecarpine, an alkaloid found in certain herbs including Evodia rutaecarpa, protects the gastric mucosa against injury induced by acetylsalicylic acid and stress, and its gastroprotective effect is related to a stimulation of endogenous calcitonin gene-related peptide release via activation of TRPV-1 being reverted by pretreatment with capsaicin or capsazepine [4]. Anandamide, a main endogenous cannabinoid endowed also with agonistic effect on TRPV-1,was able to protect gastric mucosa from injury induced by restrain stress in rats and this effect was partially mediated by sensory nerves [4]. Some pharmaceutical companies have discovered and developed potent small-molecule TRPV-1 antagonists (AZD-1386, SB-705498, MK-2295, MR-1817, JTS-653, PHE377, DWP05195, GRC6211) and tested them in Phase I–II clinical trials in search of analgesics for neuropathic, osteoarthritic, dental or esophageal pain [5]. Unfortunately, several candidate molecules showed critical side effects such as hyperthermia and impaired noxious heat sensation in humans and/or did not reach the clinical target. To overcome these drawbacks, a new class of TRPV-1 antagonists with new pharmacological profile was developed. Unlike the old ones, the new class of antagonists either maintained or partly inhibited acid activation of TRPV-1, resulting in a reduced alteration in thermosensation in preclinical tests [5]. No clinical data are available so far for them.

Topical capsaicin formulations are used for pain management. Low-concentration capsaicin formulations are found endowed with modest efficacy and require repeated daily self-administration. A high-concentration 8% capsaicin patch was recently approved in the EU and USA for neuropathic pain [6]. Likewise, a synthetic analog of capsaicin such as civamide (cis-8-methyl-N-vanillyl-6-nonenamide) given locally was able to reduce osteoarthritis pain [6]. Topical capsaicin acts on the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as ‘defunctionalization’ of nociceptor fibers. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype and reversible retraction of epidermal and dermal nerve fiber terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the TRPV-1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibers, aberrant re-innervation and collateral sprouting, all of which are defunctionalized by topical capsaicin.

Concerning the gut, the application of capsaicin to the human jejunum induced abdominal pain similar to that induced by distension [7,8]. Capsaicin did not stimulate jejunal motility nor did it affect mechanosensitivity; therefore, the altered pain sensitivity is due to stimulation of chemoreceptors, probably by the TRPV-1 activation. On the other hand, capsaicin load can be considered as a valuable test to investigate hypersensitivity. In a double-blind, placebo-controlled trial involving 116 outpatients suffering from dyspepsia, the median perception score after ingestion of capsule containing 0.75 mg of capsaicin was significantly higher than placebo [9]. In heartburn patients, 5 mg of capsaicin mixed to the meal significantly decreased the peak to the heartburn. When refluxed, capsaicin probably sensitized the esophagus and primed it to noxious stimuli such as acid [10]. Intraesophageal capsaicin infusion has been found to lower sensory and pain thresholds to esophageal balloon distension, again presumably through direct activation of TRPV-1 and release of neurotransmitters [11].

Another study has analyzed the impact of acute ingestion of red chili powder (capsaicin equivalent of 14 mg) on men diagnosed with irritable bowel syndrome (IBS) and volunteers. Chili did not alter small bowel and colonic transit in both groups but increased the rectal threshold for pain in healthy volunteers [12]. In diarrhea-predominant IBS patients, 6-week chili (2.1 g/daily) ingestion significantly decreased postprandial abdominal burning and increased the rectal sensory threshold [13]. It is noteworthy that rectal biopsy samples taken from patients with well-characterized rectal hypersensitivity showed a marked increase in TRPV-1 in muscle, submucosal and mucosal layers compared with controls [14]. Submucosal immunoreactive calcitonin gene-related peptide expressed in ganglion cells but not SP was increased as well. The increase in TRPV-1 significantly correlated with the decrease in heat and distension sensory thresholds, confirming that these fibers take part in the change of signaling pathways of visceral hypersensitivity [14]. Likewise, Akbar et al. [15,16] showed that increased TRPV-1 nerve fibers were present in quiescent inflammatory bowel disease patients with IBS-like symptoms with a correlation to pain severity. These authors observed that also substance P immunoreactivity, CD3 lymphocytes and mast cells staining for c-Kit were more prevalent in IBS patients [15]. Mediators released by endocrine and immune cells can sensitize afferent nerve endings and activate TRPV-1 since, for example, this activation is attenuated in TRPV-1 knockout mice [17].

In a recent placebo-controlled study performed in 50 IBS patients diagnosed according to Rome II criteria, the repeated administration of 600 mg/daily by enteric-coated capsules of red pepper for 6 weeks significantly decreased the intensity of abdominal pain and bloating, improving visceral sensitivity [18]. On the other hand, a study performed in healthy volunteers with the repeated ingestion of capsaicin (0.25 mg t.i.d. for 4 weeks) desensitized both chemonociceptive and mechanonoceciptive pathways [19]. In a double-blind, placebo-controlled study, 30 individuals with dyspepsia were given either 2.5 g daily of red pepper powder (divided up and taken prior to meals) or placebo for 5 weeks [20]. By the third week of treatment, individuals taking red pepper were experiencing significant improvements in pain, bloating and nausea compared to placebo, and these relative improvements lasted through the end of the study.

These antinociceptive effects were attributed to the desensitizing effect of repeated administration of capsaicin. Capsaicin produced a long-lasting refractory state during which the neurons affected are not responsive. Therefore, the repeated stimulation of TRPV-1 induced an excess of the influx of Ca⁺⁺ and other cations, sensory neurons are thus defunctionalized and depleted of their transmitter for a period of time that is the base of improvement of epigastric pain recorded. The potential clinical application of TRPV-1 agonists has to be confirmed by large clinical trials, but the mechanism of action described seems to be interesting for developing drugs in functional gastrointestinal diseases characterized by limited pharmacological armamentarium.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.