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Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol's interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca 2+ due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol. In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit's dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Purpose: Facilitatory and inhibitory responses of spinal motor neurons are influenced by somatosensory input from the skin. The purpose of this study, employing electromyography, was to examine the neuromuscular changes that occur with menthol applied to the skin over the quadriceps muscle., Methods: Forty-two healthy volunteers performed isometric knee extensions at 35% maximum voluntary contraction (MVC) in three groups (Adult Placebo, Adult Menthol, Older Adult Menthol). Stimulation used was application of 5% menthol gel to the skin. Surface electromyography (sEMG) from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) was recorded using miniature pair electrodes., Results: Root mean square electromyography (rmsEMG) in VL and VM significantly increased with menthol stimulation both in Adult and Older Adult, but no significant difference was observed between Adult Menthol and Older Adult Menthol. There was a significant decrease in mean power frequency (MPF) in VM with menthol stimulation in Older Adult, but no significant changes were observed in Adult Menthol., Conclusion: Neuromuscular modulation was observed with the application of menthol gel at low loads in the present study. These findings could lead to a new method of muscular training that targets the recruitment of fast type muscle safe for older adults.

The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure–activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA). [ABSTRACT FROM AUTHOR]

Functional biomechanical parameters of muscle soleus contraction in rats as well as selected blood biochemical parameters were studied during the first 3 days of post-traumatic syndrome progression caused by the destruction of muscle cells by compression. Single administration of the antioxidant C60 fullerene and the selective agonist of TRPM8 channels menthol were used as therapeutic agents. Injection of C60 fullerene at a concentration of 1 mg/kg into the damaged muscle improved its contractile function by 25–28%. The use of combined injections of C60 fullerene and menthol (at the concentration 1 mg/kg) improved this index by additional 27–39% and simultaneously stabilized the decrease in muscle strength observed throughout the experiment. A tendency towards a decrease in the indexes of the above described biochemical parameters by 10–15% were found with the therapeutic administration of C60 fullerene. With combined injections of C60 fullerene and menthol, the above described biochemical parameters decreased by an additional 17–24%. The synergism between the action of menthol and C60 fullerene on the post-traumatic recovery of skeletal muscle function opens up new perspectives for the clinical application of this combination therapy. [ABSTRACT FROM AUTHOR]

Aims: The transient receptor potential melastin‐8 (TRPM8) channel is a "cooling" receptor expressed in primary sensory neurons and can be activated by compounds like menthol or icilin. TRPM8 is involved in the regulation of urinary bladder sensory function and contraction, but the role of TRPM8 in the ureter, particularly in the human ureter, is poorly understood. The aim of this study is to examine the effects of TRPM8 activation on human ureter contraction. Methods: Human ureters were acquired from 20 patients undergoing radical nephrectomy. Contractions of ureter strips were recorded by an isometric transducer in the organ bath. Ureteral TRPM8 expression in the human ureter was examined by immunofluorescence and western blot. Results: The two TRPM8 agonists menthol and icilin both reduced the frequency of spontaneous, electrical field stimulation, or neurokinin A‐evoked ureteral contractions in a dose‐dependent manner. The inhibitory effects were decreased by 10‐fold in mucosa‐denuded strips. The inhibitory effects of TRPM8 agonists were mimicked by calcitonin gene‐related peptide (CGRP), and were blocked by KRP2579 (a TRPM8 antagonist), tetrodotoxin (a sodium channel blocker), olcegepant (BIBN, a CGRP receptor antagonist), SQ22536 (an adenylate cyclase antagonist), or H89 (a nonspecific cAMP‐dependent protein kinase A inhibitor). TRPM8 was coexpressed with CGRP on the nerves located in the suburothelial and intermuscular regions and was not expressed in the urothelium. Conclusions: The TRPM8 channel expressed on sensory nerve terminals of the human ureter is involved in the inhibitory sensory neurotransmission and modulate ureter contraction via the CGRP–adenylyl cyclase–protein kinase A pathway. TRPM8 may be involved in stone‐induced changes in ureter contraction or pain. [ABSTRACT FROM AUTHOR]

Both spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Transient receptor potential (TRP) vanilloid-1 (TRPV1) and melastatin-8 (TRPM8) channels play a role in transmitting sensory information in primary-afferent neurons. TRPV1 agonists at high concentrations inhibit action potential conduction in the neurons and thus have a local anesthetic effect. The purpose of the present study was to know whether TRPM8 agonist menthol at high concentrations has a similar action and if so whether there is a structure–activity relationship among menthol-related chemicals. Main methods: Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. Key findings: (−)-Menthol and (+)-menthol concentration-dependently reduced CAP peak amplitude with the IC50 values of 1.1 and 0.93mM, respectively. This (−)-menthol activity was resistant to non-selective TRP antagonist ruthenium red; TRPM8 agonist icilin did not affect CAPs, indicating no involvements of TRPM8 channels. p-Menthane, (+)-limonene and menthyl chloride at 7–10mM minimally affected CAPs. On the other hand, (−)-menthone, (+)-menthone, (−)-carvone, (+)-carvone and (−)-carveol (in each of which chemicals :glyph name="dbnd" />O group was added to p-menthane and limonene) and (+)-pulegone inhibited CAPs with extents similar to that of menthol. 1,8-Cineole and 1,4-cineole were less effective while thymol and carvacrol were more effective than menthol in inhibiting CAPs. Significance: Menthol-related chemicals inhibited CAPs and were thus suggested to exhibit local anesthetic effects comparable to those of lidocaine and cocaine as reported previously for frog CAPs. This result may provide information to develop local anesthetics on the basis of the chemical structure of menthol. [Copyright &y& Elsevier]

Abstract: The TRPM8 cation channel belongs to the superfamily of transient receptor potential (TRP) channels. It is involved in non-painful cool sensation and triggered by diverse chemical and physical stimuli whose precise activation mechanism is still unknown. The study presents a set of targeted molecular dynamics (MD) simulations involving selected complexes of the TRPM8 channel whose homology model was recently generated by some of us. More in detail, the MD simulations concerned the TRPM8 alone and in complex with agonists and antagonists. These simulations were focused on voltage sensor module and designed to validate the ligand induced activation mechanism as hypothesized in our previous study. The obtained results are in encouraging agreement with the proposed mechanism and allow a clear discrimination between agonists and antagonists. In addition, the MD runs confirm that the agonist binding triggers a set of concatenate conformational shifts which induce the approaching of the S3 segment toward the S4 segment and culminate in an extension of the latter. By introducing suitable constraints, the reported MD simulations were rendered as fast as possible in order to achieve a truly productive compromise between reliability and computational costs. The obtained results emphasize that suitably targeted MD runs can be fast enough to be systematically applied to predict the bioactivity of large datasets providing it as an useful tool in rational ligand design process. [Copyright &y& Elsevier]