A great proportion of people with Rett syndrome (RTT) have aberrant pain responses. However, due to additional RTT-related symptoms such as mobility impairments and altered verbal skills, it is difficult to assess their noxious responses. Apart of being considered a pathological state per se, altered pain responses could result in undertreatment of additional RTT-associated conditions. Here, we used male mice null for Mecp2, the gene causing most cases of RTT, to evaluate their response to an inflammatory model. At symptomatic ages (8 weeks old), two cohorts of animals received an intraplantar injection of Complete’s Freud Adjuvant. We analysed either mechanical or thermal sensitivity (von Frey hairs or Hargreaves apparatus, respectively) during basal conditions and at 1- and 3-days post-injection. An hour after last testing, animals were sacrificed and nervous tissues collected for testing. Controls included wild-type (WT) siblings and saline-injected animals from both genotypes. During basal conditions, Mecp2-null mice showed a significantly higher threshold to withdraw their paws in response to a mechanical stimulation than WT and thus are described as mechanically hyposensitive. Interestingly, although hypersensitivity also developed in the mutants at 24 hours post-injection, it was completely resolved by the third day. Immunofluorescence in sectioned brains revealed alterations in the endocannabinoid system within the Mecp2-null mice when compared to WT. Taking all together, our data suggests that MeCP2 is key player in the maintenance, but not the development, of mechanical hypersensitivity following an injury. We also point at the endocannabinoid system as a potential therapeutic target for RTT