Substance P release from spinal cord slices by capsaicin

doi:10.1016/0024-3205(79)90558-7

Life Sciences

Volume 25, Issue 7, 13 August 1979, Pages 629-636

https://doi.org/10.1016/0024-3205(79)90558-7 Get rights and content

Abstract

The release of substance P (SP) from slices of hypothalamus, substantia nigra and spinal cord of the rat was studied. In contrast to 47 mM potassium, capsaicin induced SP release from spinal cord slices only. The SP release was not reduced by 10⁻⁶ M tetrodotoxin but was abolished by a Ca²⁺ free medium containing 3 mM ethylene-glycol-bis- (β-aminoethyl-ether) N,N-tetraacetic acid (EGTA). Capsaicin induced SP release was dose-dependent and exhibited tachyphylaxis. The ability of capsaicin to release SP supports the hypothesis that SP is involved in pain transmission and in neurogenic plasma extravasation.

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Sakurada et al. observed that a short-lasting paw-licking/biting reaction following subcutaneous injection of capsaicin into the hind paw of mice was dose-dependently suppressed by morphine [128]. The stimulation of nociceptive primary afferents by capsaicin was shown to lead to the release of nociceptive neurotransmitters in the dorsal spinal cord [129,130]. Injection of BCP into the plantar surface of the hind paw dose-dependently reduced capsaicin-induced nociceptive behavior, an effect abolished by pretreatment with AM630 but not AM251.
The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R. The ligands activate CB2R are of endogenous, synthetic and plant origin. In recent years, β-caryophyllene (BCP), a natural bicyclic sesquiterpene in cannabis as well as non-cannabis plants, has received attention due to its selective agonist property on CB2R. BCP has been well studied in a variety of pathological conditions mediating CB2R selective agonist property. The focus of the present manuscript is to represent the CB2R selective agonist mediated pharmacological mechanisms and therapeutic potential of BCP. The present narrative review summarizes insights into the CB2R-selective pharmacological properties and therapeutic potential of BCP such as cardioprotective, hepatoprotective, neuroprotective, nephroprotective, gastroprotective, chemopreventive, antioxidant, anti-inflammatory, and immunomodulator. The available evidences suggest that BCP, can be an important candidate of plant origin endowed with CB2R selective properties that may provide a pharmacological rationale for its pharmacotherapeutic application and pharmaceutical development like a drug. Additionally, given the wide availability in edible plants and dietary use, with safety, and no toxicity, BCP can be promoted as a nutraceutical and functional food for general health and well-being. Further, studies are needed to explore pharmacological and pharmaceutical opportunities for therapeutic and preventive applications of use of BCP in human diseases.
Research progress of capsaicin responses to various pharmacological challenges
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Citation Excerpt :
Furthermore, these findings suggest that capsaicin causes hypertension in dogs by its action on peripheral vasculatures but not on the heart: capsaicin induced vasoconstriction is related intimately to extracellular calcium but not to an adrenergic mechanism. Release of neurotransmitters is generally considered to require the presence of extracellular Ca2+ [36,37]. Capsaicin evokes an influx of extracellular Ca2+ [38,39] possibly because of its peptide-releasing properties.
Capsaicin, a well known vanilloid, has shown evidence of an ample variety of biological effects which make it the target of extensive research ever since its identification. In spite of the fact that capsaicin causes health hazards in quite a few ways, yet, the verity cannot be ignored that capsaicin has several therapeutic implications. In patients with hypersensitive bladders, vesical instillation of 1 mM capsaicin markedly improved urinary frequency and urge incontinence. Again, administration of capsaicin favors an augmentation in lipid mobilization and a decrease in adipose tissue mass. Topical capsaicin cream as well decreases postsurgical neuropathic pain and is preferred by patients over a placebo among other therapies. Several in vitro studies have revealed that capsaicin results in growth arrest in some transformed cell lines. Furthermore, capsaicin has been proven to be an undeniably exciting molecule and remains a valuable drug for alleviating pain and itch. It has been recognized that capsaicinoids are the most potential agonists of capsaicin receptor (TRPV1). However, vanilloids could exert the beneficial effects not only through the receptor-dependent pathway but also through the receptor-independent one. The involvement of serotonin, neuropeptide Substance P and somatostatin in the pharmacological actions of capsaicin has been expansively investigated. Better understanding of the established TRPV1 receptor mechanism as well as exploring other possible receptor mechanism may publicize other new clinical efficacies of capsaicin. Further, clinical studies are required in several of these conditions to establish the efficacy of capsaicin.
Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons
2012, Neuroscience Letters
Citation Excerpt :
Thus, the Ca2+ influx mediated by activation of TRPV1 contributes to the modulation of capsaicin on PKC activity in TG neurons, which may in turn induce a positive feedback enhancement of TRPV1 activity. It has been demonstrated that capsaicin can induce SP release in vivo and in vitro experiments [1,6,21,28]. Consistent with these results, we also found SP release by TRPV1 receptor activation depended on extracellular Ca2+.
Intracellular second messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca²⁺ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca²⁺ dependency in the signal transduction of capsaicin-induced desensitization. On the average, capsaicin increased cAMP, cGMP concentration and SP release in bell-shaped concentration-dependent manner, with the maximal responses at concentrations around 1 μM, suggesting acute desensitization of TRPV1 receptor activation. Capsaicin-induced intracellular Ca²⁺ concentration ([Ca²⁺]_i) increase depended on extracellular Ca²⁺ influx as an initial trigger. The Ca²⁺ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca²⁺-free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca²⁺-dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca²⁺ removal, suggesting at least in part a Ca²⁺-independent pathway is involved. Further study showed that cAMP increase was totally abolished by G-protein and adenylate cyclase (AC) antagonist, suggesting a G-protein-dependent pathway in cAMP increase. However, SP release was blocked by inhibiting PKC, but not G-protein or AC, suggesting a G-protein independent pathway in SP release. These results suggest that both Ca²⁺-dependent and independent mechanisms are involved in the regulation of capsaicin on second messengers systems, which could be a novel mechanism underlying distinct desensitization of capsaicin and might provide additional opportunities in the development of effective analgesics in pain treatment.
Inhibition of ERK phosphorylation by substance P N-terminal fragment decreases capsaicin-induced nociceptive response
2011, Neuropharmacology
Citation Excerpt :
Numerous studies have documented the presence of substance P in sensory afferent fibers in the dorsal root ganglia and the dorsal horn of the spinal cord (Pernow, 1983). Substance P is released from the spinal cord following various nociceptive stimuli (Duggan et al., 1987; Kantner et al., 1985; Schaible et al., 1990) and administrations of capsaicin through peripheral and intrathecal (i.t.) routes (Gamse et al., 1979; Go and Yaksh, 1987). Following release and binding to neurokinin1 (NK1) receptor, the biological action of substance P is terminated by enzymatic degradation (Lee et al., 1981; Matsas et al., 1984; Nyberg and Terenius, 1991).
Previous research has demonstrated that substance P N-terminal fragments produced by the action of several different enzymes in the spinal cord could reduce nociception when injected intrathecally (i.t.) into mice. The present study examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK), a mitogen-activated protein kinase (MAPK), in i.t. substance P (1–7)-induced antinociception as assayed by the capsaicin test. The i.t. injection of substance P (1–7) (20–80 nmol) into mice resulted in a dose-dependent attenuation of paw-licking/biting behavior induced by intraplantar injection of capsaicin, which was reversed by co-injection of [d-Pro², d-Phe⁷]substance P (1–7), a d-isomer and antagonist of substance P (1–7). In Western blot analysis, intraplantar injection of capsaicin (400 and 1600 ng/paw) produced an increase of ERK phosphorylation in the dorsal spinal cord, whereas expression of p38 and c-Jun N-terminal kinase (JNK) phosphorylation was unchanged by capsaicin treatment. In parallel to the behavioral results, i.t. substance P (1–7) inhibited capsaicin-induced EKR phosphorylation, which was reversed by [d-Pro², d-Phe⁷]substance P (1–7), a substance P (1–7) antagonist. Both nociceptive behavioral response and spinal ERK activation induced by intraplantar capsaicin were reduced by U0126, an upstream inhibitor of ERK phosphorylation. Taken together, these findings suggest that the activation of ERK, but not p38 and JNK MAPKs in the spinal cord, contributes to intraplantar capsaicin-induced nociception, and that blocking ERK activation via substance P (1–7) binding sites may provide significant antinociception at the spinal cord level.
Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism
2011, Pharmacology Biochemistry and Behavior
Citation Excerpt :
We previously reported that subcutaneous (s.c.) injection of capsaicin into the hindpaw produced a short-lasting paw-licking/biting response, which was dose-dependently inhibited by intrathecally (i.t.) administered morphine (Sakurada et al., 1994). Activation of primary afferent nociceptors by capsaicin causes the release of nociceptive transmitters, substance P and glutamate from the dorsal spinal cord in vivo and in vitro (Gamse et al., 1979; Ueda et al., 1993; Sorkin and Mcadoo, 1993). In addition, it has been shown that capsaicin excites the C-fiber population of nociceptive afferents through transient receptor potential vanilloid type-1 (TRPV-1) receptors located in C-fiber type nociceptors (Di Marzo et al., 2002; Szallasi et al., 2007).
This study investigated the effect of bergamot essential oil (BEO) containing linalool and linalyl acetate as major volatile components in the capsaicin test. The intraplantar injection of capsaicin (1.6 μg) produced a short-lived licking/biting response toward the injected paw. The nociceptive behavioral response evoked by capsaicin was inhibited dose-dependently by intraplantar injection of BEO. Both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal (i.p.) and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly reversed BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting μ-opioid receptor preferring antagonist, resulted in a significant antagonizing effect on antinociception induced by BEO and linalool. Antinociception induced by i.p. or intrathecal morphine was enhanced by the combined injection of BEO or linalool. The enhanced effect of combination of BEO or linalool with morphine was antagonized by pretreatment with naloxone hydrochloride. Our results provide evidence for the involvement of peripheral opioids, in the antinociception induced by BEO and linalool. Combined administration of BEO or linalool acting at the peripheral site, and morphine may be a promising approach in the treatment of clinical pain.
Pain and learning in a spinal system: Contradictory outcomes from common origins
2009, Brain Research Reviews
The long-standing belief that the spinal cord serves merely as a conduit for information traveling to and from the brain is changing. Over the past decade, research has shown that the spinal cord is sensitive to response–outcome contingencies, demonstrating that spinal circuits have the capacity to modify behavior in response to differential environmental cues. If spinally transected rats are administered shock contingent on leg extension (controllable shock), they will maintain a flexion response that minimizes shock exposure. If, however, this contingency is broken, and shock is administered irrespective of limb position (uncontrollable shock), subjects cannot acquire the same flexion response. Interestingly, each of these treatments has a lasting effect on behavior; controllable shock enables future learning, while uncontrollable shock produces a long-lasting learning deficit. Here we suggest that the mechanisms underlying learning and the deficit may have evolved from machinery responsible for the spinal processing of noxious information. Experiments have shown that learning and the deficit require receptors and signaling cascades shown to be involved in central sensitization, including activation of NMDA and neurokinin receptors, as well as CaMKII. Further supporting this link between pain and learning, research has also shown that uncontrollable stimulation results in allodynia. Moreover, systemic inflammation and neonatal hindpaw injury each facilitate pain responding and undermine the ability of the spinal cord to support learning. These results suggest that the plasticity associated with learning and pain must be placed in a balance in order for adaptive outcomes to be observed.

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Substance P release from spinal cord slices by capsaicin

Abstract

Brit. J. Pharmac.

Brain Res.

Naunyn-Schmiedeberg's Arch. Exp. Path. Pharmak.

Brain Res.

Nature

Acta Physiol. Scand.

Brain Res.

Med. exp.

Brain Res.