TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye

Abstract

PurposePersistent ocular surface pain occurs in moderate to severe dry eye disease (DE); however, the mechanisms that underlie this symptom remain uncertain. The aim of this study was to determine if the transient receptor potential vanilloid ion channels play a role in hypertonic saline (HS)-evoked corneal reflexes in a model for aqueous tear deficient DE.MethodsEye wipe behavior and orbicularis oculi muscle activity (OOemg) were measured after ocular instillation of HS, capsaicin, or menthol 14 days after exorbital gland removal. Total RNA and protein were measured from anterior eye segment and trigeminal ganglia of sham and DE rats.ResultsEye wipe behavior was enhanced in DE rats after HS and capsaicin instillation, but not after menthol when compared to sham rats. DE rats displayed greater OOemg activity after HS and capsaicin, but not after menthol, compared to sham rats. HS-evoked OOemg activity was reduced by selective TRPV1 antagonists and by coapplication of capsaicin plus QX-314, a charged lidocaine derivative. Menthol did not affect OOemg activity; however, selective antagonism of TRPM8 reduced HS-evoked OOemg activity. TRPV1 protein levels were increased in anterior eye segment and trigeminal ganglion samples from DE rats, whereas TRPM8 levels were not affected.ConclusionsThese results suggest that TRPV1 plays a significant role in mediating enhanced nocifensive behavior in DE, while TRPM8 may play a lesser role. Strategies to target specific transducer molecules on corneal nerves may prove beneficial as adjunct therapies in managing ocular pain in moderate to severe cases of DE.

Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors

“…The reduction in palpebral opening after unilateral LGE was restricted to the side ipsilateral to the excision. This result is similar to the ipsilateral increase in blinking observed in the rat after LGE 11,15,32,37 and suggests that unilateral LGE-induced corneal injury mainly affects ongoing sensitivity on the ipsilateral cornea. A systematic evaluation of the contralateral cornea after LGE that includes testing mechanical and chemical sensitivity has not yet been performed.…”

“…The sensitization of polymodal corneal afferents is consistent with the increased eye wipe response observed after LGE in response to hypertonic saline in male rats 11,15 . In addition, unilateral LGE increased mechanical sensitivity and spontaneous blinking in the ipsilateral compared to contralateral eye in male rats.…”

“…Eye wipe behaviors are a common nocifensive response that have been used to assess corneal sensitivity to noxious stimuli 43 . Previous studies have shown an increase in eye wipe behaviors following LGE in male rats in response to hypertonic saline and capsaicin 11,15 . In contrast to these results, Hegarty et al 44 found no changes in capsaicin eye wipe behaviors after lacrimal gland denervation in male rats.…”

“…In addition to increased eye wipe behavior, hypertonic saline and capsaicin-evoked orbicularis oculi muscle activity (OOemg) were increased in rats following LGE 15 . The hypertonic-saline evoked OOemg activity was blocked by TRPV1 antagonists and partially attenuated by a TRPM8 antagonist.…”

“…Aqueous tear deficiency, a form of dry eye caused by insufficient tear production from the lacrimal glands, has been modeled in the rodent through excision or functional disruption of the lacrimal glands [8][9][10][11][12][13][14] . Lacrimal gland excision (LGE) has been demonstrated to sensitize corneal polymodal nociceptive neurons to the TRPV1 agonist capsaicin and low pH induced by CO 2 , as well as sensitize corneal cold cells to the TRPM8 agonist menthol 11,[15][16][17] . Furthermore, LGE-induced plasticity in corneal afferents includes an increase in co-expression of TRPM8 and TRPV1, which is matched by a greater proportion of cold responsive corneal afferents that are activated by noxious heat after LGE 18 .…”