Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination

Abstract

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced antinociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore-or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.Key words alpha-2 adrenoceptor; clonidine; sigma-1 receptor; orofacial pain; formalin testThe orofacial region is one of the most densely innervated, by the trigeminal nerve, areas of the body, which focuses some of the most common acute pains, i.e., those accompanying the pathological states of the teeth and the related structures.1) It is also the site of frequent chronic post-herpetic neuralgia, migraine, and referred pains. However, only few analgesic trials have been undergone in trigeminal region, and a lot of difficulties in the management of acute and chronic orofacial pain conditions stem from a lack of recognition and understanding of pain mechanisms. 2,3) In this regard, the management of orofacial disorders is one of the most challenging in the pharmacology field in relation to analgesics.It is well established that an alpha-2 adrenoceptor agonist, clonidine significantly attenuates nociception and hyperalgesia in acute and chronic pain animal models.4,5) Alpha-2 adrenoceptor agonists are thought to produce analgesia primarily by actions in the spinal cord, both by reducing the release of glutamate and substance P from central afferent terminals 6,7) and by hyperpolarizing dor...

Tizanidine exerts anti-nociceptive effects in spared nerve injury model of neuropathic pain through inhibition of TLR4/NF-κB pathway

“…Peripheral neuropathic pain is produced by multiple etiological factors, and spared nerve injury (SNI) is an important model for exploring the cellular and molecular mechanism in peripheral neuropathic pain ( 1 , 2 ). It has been demonstrated that the agonists of α2-adrenoceptors (α2-AR) have anti-nociceptive effects ( 3 , 4 ). Tizanidine, a derivative of clonidine, is a highly selective agonist of α2-AR, and has the same effects of clonidine, but the side effects such as low arterial blood pressure and bradycardia are lower ( 5 , 6 ).…”

Investigation of noradrenergic receptor system in anti-nociception using formalin test in the naked mole rat (Heterocephalus glaber)

“…Intraperitoneal administration of clonidine under formalin test responds in a similar dose dependent manner in mice and rats ( Yoon et al., 2015 ; Fukuda et al., 2006 ). Clonidine administration intrathecally also shows similar dose dependent responses under formalin test in the African marsh terrapin ( Pelomedusa subrufa ) and Speke's hinged tortoise ( Makau et al., 2014 , 2016 ); mice ( Kanui et al., 1993 ), and Sprague-Dawley rats ( Yoon et al., 2009 ).…”

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation

“…The S1R is a non-opioid chaperone receptor located in the plasm membrane of the endoplasmic reticulum (Hayashi and Su, 2003) expressed in regions associated with pain regulation, such as dorsal root ganglia, spinal cord, thalamus, and rostroventral medulla of female mice (Sánchez-Fernández et al, 2014) and the spinal cord, thalamus, and sciatic of male rats (Alonso et al, 2000). S1R is reported in the trigeminal ganglia of male mice (Yoon et al, 2015), but expression in female trigeminal sensory neurons currently unknown. Activation of S1R elicits nociceptive responses, which can be reversed with SR1 antagonists (Kim et al, 2008;Gris et al, 2014;Parenti et al, 2014;Pyun et al, 2014;Roh and Yoon, 2014;Tejada et al, 2014;Entrena et al, 2016) or in S1R knockout mice (Entrena et al, 2009;de la Puente et al, 2009).…”