As a way to study the consequences of damage in trigeminal nerve branches in non-human primates, we established a nerve injury model of maxillary nerve compression (MNC) in the cynomolgus macaque monkey, Macaca fascicularis. This is the first reported study of maxillary nerve injury model in non-human primates. Our hypothesis was that, because non-human primates show similarities to human in facial anatomy and facial nerve organization, whereas facial anatomy of rodents differs much from that of human, a maxillary nerve injury model in non-human primates will help to advance understanding of the consequences of facial nerve injury. The nerve injury from the compression appeared to be mild, as we did not observe overt changes in home-cage behavior in the monkeys.
When mechanical stimulation was applied to the facial area, monkeys with MNC displayed increased mechanical sensitivity, as the avoidance response scores were lower than those from the control animals (Figure 1B). It is noteworthy that such a change in mechanical sensitivity was evident bilaterally, even though the MNC surgery was performed unilaterally. Noteworthy is the fact that the ipsilateral side showed a more robust change, with scores significantly different from both the control and the contralateral side (Figure 1B). In rodent models of damages to trigeminal nerve branches, it has been reported that a decrease in mechanical threshold was observed bilaterally, with the ipsilateral side showing stronger sensitization than the contralateral side in rats receiving chronic constriction injury to the infraorbital nerve [1, 6–8]. Also, similar results were obtained by photochemical reaction-induced partial ischemic injury to the infraorbital nerve in rats . Our results in monkeys are consistent with these reports in rodents, and suggest that unilateral damage to the maxillary nerve caused bilateral changes in mechanical sensitivity, with the ipsilateral side displaying a more robust change compared to the contralateral side.
Another potential contributor to the altered somatic sensation could be from the surgical wound and accompanying inflammation. We did not observe visible inflammation, and the animals appeared not to be bothered by the surgical wound, as they did not display excessive scratching or touching of the surgical site on the face while going about with their daily activities. Also, at the time of behavioral testing, the surgical incision appeared to about to heal. Further, the somatic sensation was tested by gently brushing the areas above the lips, not at the surgical incision site over infraorbital foramen (see diagram in Figure 1A). Thus, it appears unlikely that surgical wound played a major part in altering the somatic sensation.
We also observed an effect of MNC injury on the maxillary nerve’s electrophysiological properties. Multiple-unit recording of nerve fiber bundles of the maxillary nerve was obtained from the contralateral side of two MNC monkeys, and from both sides of two MNC monkeys. As shown in Figure 2, a general trend of elevated electrical response to escalating force in mechanical stimulation was observed for the contralateral side of the maxillary nerve, with four of the five animals displaying this pattern. This suggests that the contralateral maxillary nerve in MNC model retained its electrophysiological responsiveness to mechanical stimulation applied to the receptive field. On the other hand, the maxillary nerve on the ipsilateral side displayed minimum responsiveness, as the firing rate showed rather flat response profiles (Figure 2). This indicates that after MNC injury, the ipsilateral maxillary nerve become non-responsive to mechanical stimulation applied to its receptive field.
For the ipsilateral maxillary nerve, the lack of responsiveness at the electrophysiological level is likely the consequence of MNC injury. There are two possible explanations. One is that the nerve was sensitized by the MNC injury, so that even a slight mechanical stimulation with a low force von Frey filament would cause maximum firing, therefore there was no room for further increase in electrophysiological response when the stimulation intensity escalated. Alternatively, the maxillary nerve was desensitized after the MNC injury, so that it became non-responsive to stimulation. Based on the electrophysiological data alone, it is difficult to distinguish between these mutually exclusive explanations, because the absolute values of the electrophysiological data are not directly comparable with one another, due to the fact that each nerve bundle in an electrophysiological recording had a different number of nerve fibers. However, behavioral response to mechanical stimulation offered certain clues. The ipsilateral side of the MNC surgery was more sensitive to brushing test (Figure 1B), indicating that the MNC surgery side of the face was responsive at behavioral level. This suggests that it is unlikely that the MNC side of the maxillary nerve was desensitized. It seems more likely that MNC injury resulted in a state of sensitization of the nerve at the electrophysiological level, possibly with a much reduced threshold for maximum electrical response, such that even a low intensity of stimulation to the receptive field elicited near-maximum responses of the nerve, thus giving a rather flat response profile in relation to stimulation intensity (Figure 2).
In future studies, it would be informative to examine the development of electrophysiological changes with time, with a large number of study subjects, so at different time points several monkeys could be used for electrophysiological recordings, and a time course of electrophysiological changes could be documented.
It should be noted that, compared with studies in rodent models, the monkeys used in this study were relatively heterogeneous with regard to their breeding lineage, as they were not from an established breeding colony; rather, they were bred at the laboratory animal supplier’s facility from parental monkeys captured in the wild. As such, individual variability is expected, as demonstrated by the electrophysiological response profile of monkey #2, which was different from the general pattern observed in the other monkeys (Figure 2).