NSAIDs attenuate hyperalgesia induced by TRP channel activation

Abstract

Transient receptor potential (TRP) cation channels have been extensively investigated as targets for analgesic drug discovery. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins (mediators of inflammation) and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we examined three widely used NSAIDs (diclofenac, ketorolac, and xefocam) on the activation of TRPA1 and TRPV1 channels using thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test in male rats. Thermal withdrawal latencies and mechanical thresholds for both hind paws were obtained with 5, 15, 30, 45, 60, and 120 min intraplantar post-injection of TRPA1 agonizts, allyl isothiocyanate (AITC) (a natural compound of mustard oil) and cinnamaldehyde (CA), and TRPV1 agonist capsaicin or vehicle. Twenty minutes prior to the start of the experiment with TRP agonizts, diclofenac, ketorolac or xefocam were pre-injected in the same hindpaw and animals were examined by these two tests. After pretreatment of all three NSAIDs in the ipsilateral (injected) hindpaw that produced strong antinociceptive effects, AITC, CA, and capsaicin caused significant decreases in latency of the thermal withdrawal reflex compared with vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold. In approximately 30 min the effects of CA, AITC, and capsaicin returned to baseline. The data are different from our previous evidence, where TRPA1 agonizts AITC and CA and TRPV1 agonist capsaicin produced hyperalgesia for nearly 2 h and resulted in facilitation of these withdrawal reflexes (Tsagareli et al., 2010, 2013). Thus, our data showing that NSAIDs suppress thermal and mechanical hyperalgesia following TRP activation could presumably due to inactivation or desensitization of TRPA1 and TRPV1 channels by NSAIDs.

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review

“…Other drugs acting via TRPV1 include NSAIDs such as diclofenac, ketorolac, and xefocam. These molecules applied topically in rats inhibited pain behavior, most probably by inhibition of TRPV1 and TRPA1 channels [ 169 ]. Endocannabinoids and phyto-cannabinoids may exert their antinociceptive effect via TRPV1 activation, as was shown in preclinical studies.…”

“…Topically administered NSAIDs may interfere with the nociceptive pathway by their ability to decrease the synthesis of proinflammatory PGs through inhibition of cyclooxygenase COX-2. Preclinical studies showed that locally administered diclofenac may also act on several ion channels (Nav, TRPV1, TRPA1, TRPM3, K + , NMDAR) at peripheral neurons, resulting in antinociception [ 138 , 169 , 226 , 228 , 229 ]. Peripheral antinociception induced by diclofenac may rely on release of noradrenaline and interaction with α1, α2C, and β-adrenoreceptors [ 230 ].…”

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity—A Structured Review

“…Many other compounds, drugs, and chemicals are thought to interact with TRP channels. Based on TRPA1-induced hyperalgesia, Nozadze et al investigated nonsteroidal anti-inflammatory drugs with regard to their potential to counteract TRPA1-induced side-effects [ 68 ]. In the in vivo study, diclofenac, ketorolac, and xefocam have proven to diminish AITC-induced TRPA1 activation, and hyperalgesia was mitigated [ 68 ].…”

Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls

“…Notably, capsaicin, the main active ingredient of hot chili peppers, is a potent, highly selective TRPV1 agonist, and a capsaicin 8% patch relieves pain in patients with peripheral neuropathic pain [29] (Table 1). Interestingly, NSAIDs also appear able to desensitize TRPV1 channels—a mechanism supposed to participate in the NSAID-mediated attenuation of hyperalgesia [30].…”