Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations

Abstract

Background: Social touch constitutes a key component of human social relationships although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.Methods: In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors.Results: Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.Conclusions: Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.Funding: Key Technological Projects of Guangdong Province grant 2018B030335001.Clinical trial number: NCT05265806.

Oromucosal Administration of Oxytocin: The Development of ‘Oxipops’

“…While there is still the possibility that some functional effects of the intranasal administration of oxytocin might be mediated via its direct entry into the brain via the olfactory and trigeminal nerves, which could not be achieved by an oromucosal route, evidence to date supports the conclusion that many functional effects are mediated by increased blood concentrations [ 4 , 16 , 33 , 34 , 35 , 40 , 50 ]. Most notably, in a recent study where the ability of intranasally administered oxytocin to enter the peripheral circulation was greatly reduced by the pre-administration of a vasoconstrictor (otrivine), the functional effects of a 24 IU intranasal oxytocin dose were almost completely eliminated.…”

“…The same protocol was therefore adopted as for intranasal administration with 6 × 4 IU doses being self-administered under and on top of the tongue and with each spray being given at 30 s intervals to match the intranasal protocol (i.e., a total administration duration of 3 min). To maximize absorption, subjects were required to keep the spray in their mouth without swallowing until they self-administered the next dose [ 33 , 34 , 35 ]. Initially, in these studies, a pharmacokinetic assessment was carried out in 10 male adult male subjects with blood samples being taken at 15 min intervals before and for 105 min after the lingual administration.…”

“…** p < 0.01, for post-hoc tests following significant ( p < 0.001 for both AUC and bioavailability) one-way ANOVAs (Kruskall–Wallis). Data are taken from [ 16 , 33 , 39 ]. For bioavailability calculations, plasma concentrations of oxytocin following intravenous infusions are taken from a publication by another group who have made their data publically available [ 15 ].…”

“…However, overall, lingual and intranasal oxytocin both appeared to influence neural responses to emotional faces, although with some route-dependent differences which might possibly have been due to the fact that increased oxytocin concentrations were greater after intranasal, compared to lingual, administration. Additionally, 24 IU of both intranasal and lingual oxytocin produce a similar facilitation of the perceived pleasantness of soft, caress-like touch, but not of medium pressure touch, as well as increased responses in brain reward (orbitofrontal cortex) and social cognition (superior temporal gyrus) processing regions [ 33 ]. Finally, a series of studies investigating the effects of oxytocin on top-down compared with bottom-up attention control found equivalent effects of 24 IU doses administered intranasally, lingually, and via ‘oxipops’ on top-down attention control, particularly in relation to social stimuli but also to some extent for non-social ones, using an anti-saccade task [ 35 , 40 ].…”

Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders

“…However, it has been found that the nose-to-blood route is more critical for the pharmacological effects of nasal OXT than the nose-to-brain route, and that nasal OXT produces its effects by increasing peripheral blood concentrations rather than directly entering the brain in the human subject [ 44 ]. In addition, Chen et al also confirmed that oral and nasal spray OXT increased peripheral circulating concentrations [ 45 ]. OXT selectively enhances C-touch fiber-targeted pleasurable responses to social touch processing via peripheral pathways rather than directly into the brain [ 45 ].…”