Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain

Rodríguez‐Palma, Erick J.; Castelo-Flores, Dania Guadalupe; Caram-Salas, Nadia L.; Salinas-Abarca, Ana Belen; Centurión, David; Luz-Cuellar, Yarim Elideth De la; Granados‐Soto, Vinicio

doi:10.1016/j.ejphar.2022.174855

Cited by 7 publications

(7 citation statements)

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“…According to Figures 3A–C i.t., JP 1302 was unable to block clonidine’s effect. Similar results were found in a neuropathic pain model ( Rodríguez-Palma et al, 2022 ) or writhes-induced by sleep deprivation ( Yaoita et al, 2018 ), showing that systemic JP 1302 does not preclude the behavioral antinociceptive action of α 2 -adrenoceptor agonists (ST-91 or tizanidine given systemically). However, when we analyzed the per se effects of the antagonist ( Figures 3D–F ), we found that in sharp contrast to BRL 44408 or imiloxan, i.t., JP 1302 diminishes the number of flinches induced by formalin (in phase I and II), implying that this antagonist has an antinociceptive effect during the formalin test.…”

Section: Discussionsupporting

confidence: 71%

“…For example, in an inflammatory pain model, Zhang et al (2012) showed that spinal α 2B -adrenoceptor blockade with imiloxan does not reverse the antinociception induced by enhancement of the descending noradrenergic tone, suggesting that this receptor subtype is not necessary for the noradrenergic analgesic effect. However, in neuropathic pain models involving ligature of spinal nerves (not tested in the present experiments) and using selective ligands, it seems that α 2B -adrenoceptor acquire a role in the inhibition of nociception ( Chu et al, 2015 ; Rodríguez-Palma et al, 2022 ) an effect probably related with cortical activation of this receptor subtype rather than spinal mechanism ( Chu et al, 2015 ). In essence, our data suggest that spinal α 2B -adrenoceptor does not play a role in tonic inflammatory and acute nociception.…”

Section: Discussionmentioning

confidence: 69%

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The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat

et al. 2022

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Spinal α2-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to Gi/o proteins can be subdivided into three functional subtypes: α2A, α2B, and α2C-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α2A and seems to exclude the role of α2B, but the functional contribution of α2C-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α2-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective α2A/α2B/α2C-adrenoceptor agonist) and/or selective subtype α2-adrenoceptor antagonists on: 1) tonic nociception induced by subcutaneous formalin (flinching behavior) or 2) acute nociception induced by peripheral electrical stimulus in in vivo extracellular recordings of spinal dorsal horn second-order wide dynamic range (WDR) neurons. Clonidine inhibited the nocifensive behavior induced by formalin, an effect blocked by BRL 44408 (α2A-adrenoceptor antagonist) but not by imiloxan (α2B-adrenoceptor antagonist) or JP 1302 (α2C-adrenoceptor antagonist). Similarly, spinal BRL 44408 reversed the clonidine-induced inhibition of nociceptive WDR activity. Interestingly, spinal JP 1302 per se produced behavioral antinociception (an effect blocked by bicuculline, a preferent GABAA channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α2A-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α2C-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α2A and α2C-adrenoceptors modulating nociception.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 69%

The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat

et al. 2022

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“…Differences in pain signaling regulation between male and female rodents under physiological and pathological conditions have been widely studied. 1,19,41,47,48,53,58,60,61,68–70 In this study, we observed that both PAMs of the α 6 -containing GABA A receptor (Ro 15-4513 and PZ-II-029) induced a greater antiallodynic effect in female compared with male neuropathic rats and mice. Interestingly, we also observed that the α 6 -containing GABA A receptor antagonist furosemide induced greater mechanical hypersensitivity in female rats than in male naive rats.…”

Section: Discussionmentioning

confidence: 59%

“…56 Our data advances the idea that reducing the activity of GABA A receptors with pharmacological or molecular tools leads to nociception in naive animals. 6,12,19,27,41,43,60 It has been widely reported that GABA A receptors expressed in the spinal cord regulate sensory information. 13,19,27,29,80 Previous work has shown that the a 6 subunit is expressed in lamina II of the spinal dorsal horn.…”

Section: Discussionmentioning

confidence: 99%

Activation of α6-containing GABAA receptors induces antinociception under physiological and pathological conditions

Rodríguez‐Palma

Luz-Cuellar

Islas-Espinoza

et al. 2022

Pain

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“…The antiallodynic effect of tizanidine in female neuropathic rats is due to the activation of adrenergic α2A/2B receptors, but in male neuropathic rats it is due to the activation of opioid receptors. 22 Pei et al demonstrated that tizanidine has anti-nociceptive effects in spared nerve injury model of neuropathic pain by inhibiting the activation of TLR4/NF-κB p65 signaling pathway and subsequently suppressing the production of pro-inflammatory cytokines. 23 …”

Section: Resultsmentioning

confidence: 99%

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

Zhu,

Wang,

Zhou

2024

JPR

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Background Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria ® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Methods Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Results Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer’s disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Conclusion Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

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Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain

Cited by 7 publications

References 50 publications

The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat

The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat

Activation of α6-containing GABAA receptors induces antinociception under physiological and pathological conditions

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

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