Oxaliplatin, which is used as one of anti-cancer drugs, commonly induces peripheral neuropathic pain. We have previously reported that an injection of diluted bee venom (DBV) produced a significant anti-nociceptive effects in several pain models of mice or rats. In this study, we evaluated time- and dose-dependent development of oxaliplatin-induced mechanical allodynia in bilateral hind paws of mice, and investigated the effect of DBV injection on this mechanical allodynia. DBV (0.1 mg/kg) was subcutaneously injected into the Zusanli acupoint 2 weeks after oxaliplatin (10 mg/kg) injection. One hour after DBV injection, we observed a significant reduction of mechanical allodynia in the ipsilateral hind paw, but not in the contralateral hind paw to DBV injection site. We subsequently examined whether this effect of DBV was related to the activation of peripheral nerves in DBV injected site, and then whether it was mediated by the activation of spinal cord alpha-2 adrenoceptors or opioid receptors. Subcutaneous pre-injection of 2% lidocaine (40 mg/kg) into the Zusanli acupoint completely blocked the anti-allodynic effect of DBV. Intrathecal pretreatment with yohimbine (25 µg/mouse), an alpha-2 adrenoceptor antagonist, also prevented the anti-allodynic effect of DBV, whereas pretreatment with naloxone (20 µg/mouse), an opioid receptor antagonist, did not block the effect of DBV. Taken together, these findings demonstrate that DBV injection into the Zusanli acupoint significantly reduces ipsilateral mechanical allodynia generated by oxaliplatin in mice, and also suggest that this anti-allodynic effect is dependent on the peripheral nerve activation in injected site and spinal cord alpha-2 adrenoceptors.
Administration of dexmedetomidine significantly induces sedation and anti-nociception in several nociceptive models, but clinical trials are restricted due to adverse side effects, including lethargy, hypotension, and bradycardia. Herein, we investigated whether intraperitoneal inoculation of dexmedetomidine reduced the orofacial nociceptive response and affected motor coordination and blood pressure and examined whether a lower dose of dexmedetomidine in combination with 0.5% lidocaine produced an antinociceptive effect without any adverse side events in a murine model. To perform the experiment, 5% formalin (10 µL) was subcutaneously inoculated into the right upper lip, and the rubbing responses were counted for 45 min. Different doses of dexmedetomidine combined with 0.5% lidocaine were administered 10 and 30 min before formalin injection, respectively. Dexmedetomidine (10 μg/kg) significantly reduced orofacial nociceptive responses during the second phase of the formalin test and decreased the expression of Fos in trigeminal nucleus caudalis (TNC). Besides, a high dose of dexmedetomidine (30 μg/kg) induced lessening physical ability and significantly reduced systolic pressure and heart rate. When 0.5% lidocaine was injected subcutaneously, nociceptive responses were reduced only in the first phase. Interestingly, although a low dose of dexmedetomidine (3 μg/kg) alone did not show an antinociceptive effect, its co-administration with lidocaine significantly reduced the nociceptive response in both phases and decreased TNC Fos expression without motor dysfunction and hypotension. This finding suggests that the combination of a low-dose of systemic dexmedetomidine with lidocaine may be a safe medicinal approach for acute inflammatory pain management in the orofacial region, particularly mucogingival pain.
The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.
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