Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction‐induced thermal hyperalgesia in an operant assay

Abstract

Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 °C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P < 0·05). Complete reversal of thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 °C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.

Botulinum toxin A, brain and pain

“…These effects were proposed to contribute to analgesic activity of BoNT/A in neuropathic pain. In a model of chronic constriction injury of the infraorbital nerve, BoNT/A reduced the mechanical allodynia and thermal hyperalgesia (Kitamura et al, 2009;Filipović et al, 2012;Kumada et al, 2012). Along with its analgesic activity, it also reduced the accompanying neurogenic inflammation of cranial dura mater (Filipović et al, 2012).…”

Basic research and clinical investigations of the neural basis of orofacial pain

“…Intradermal injections of BoNT/A into the infraorbital branch of the trigeminal nerve decreased the ION-CCI-induced mechanical allodynia and reduced the exaggerated FM4-64 release from TG neurons (Fig. 3) [20], suggesting that BoNT/A decreases neuropathic pain behavior by decreasing neurotransmitter release from TG sensory neurons [19,20].…”

“…*P o 0.05 and **P o 0.01 between the time point of 7 days after the IoNC and 7 days after the BoNT/A injection. This figure is modified from Ref [20]. with permission.…”

OnabotulinumtoxinA for trigeminal neuralgia: a review of the available data

“…A: before BoNT/A treatment the average pain areas were 2.06 cm In animal models in which constriction of the infraorbital nerve produces tactile allodynia with increased expression of FM4-64 44 and thermal hyperalgesia 45 , both dysfunctions are easily inhibited with prior use of BoNT/A.…”

“…Peripheral lesion causing nociceptive activation of transient receptor potential (TRP) channels, a calcium influx to the cell and secondary activation with release of substance P, CGRP and glutamate. Activation of sympathetic fibers with release of norepinephrine (NE) and adenosine triphosphate (ATP); C: Application of BoNT/A with intracellular influx and blocking of TRP expression, inhibiting the release of substance P, CGRP and glutamate 43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58 . Figure 2.…”