Recently, a number of groups have validated a modified version of the conditioned place preference, aCPP, in the post hoc analysis of known human analgesic agents. aCPP is an important new variation on the classic conditioned place preference that has been used for over 30 years to study drugs of abuse. In the aCPP model, animals receive a nociceptive injury prior to testing. Next, pairing with known or unknown analgesic agents occurs. Animals develop a preference for the drug-paired chamber only if they receive relief from on-going or spontaneous nociception or other negative stimulation. Other groups have shown that both mGluR1 and mGluR5 antagonism inhibit the development of classic CPP to stimulant or rewarding drugs in naive rats and mice. Here, we show for the first time that systemic mGluR5 inhibition with fenobam or MPEP induces aCPP only in the context of a neuropathic injury, SNI. Both male and female SNI-operated mice developed a preference for the chamber paired with the mGluR5 antagonist. SNI mice spend a greater amount of time in the mGluR5 antagonist-paired chamber, compared to the vehicle chamber on day 5. In addition to this, there is also a significant increase in the time spent in the mGluR5 antagonist chamber on day 5 compared to the baseline day 1. In contrast, male and female sham-operated mice show no Talazoparib statistically significant difference in the amount of time spent in the mGluR5 antagonist-paired chamber, when compared to the vehicle-paired chamber. These data suggest that mGluR5 antagonism is rewarding only in the context of SNI and that the rewarding effect may be caused by analgesia. The failure of both fenobam and MPEP to induce statistically significant preference in sham animals indicates that these drugs have a low potential for rewarding or deleterious effects in the absence of injury. In addition, this also highlights the value of aCPP as a screening paradigm. Avoiding agents that induce preference in naive or sham-operated mice may reduce the chance of addiction in humans. One additional aspect addressed in our studies is the fact that fenobam was able to produce preference in both male and female mice. This is important because there are many differences in pain condition prevalence between men and women. For example, fibromyalgia and interstitial cystitis have been found to be much more prevalent in women compared to men. Despite this, many basic science studies only test male animals, neglecting the potential differences that could be found with females. It is important to include both groups in studies in order to determine if the effects can be replicated in both men and women. Here, we were able to show that there were no sex differences between males and females regarding both fenobam and morphine aCPP. This suggests that mGluR5 antagonism with fenobam may be an effective strategy to broadly treat pain in both sexes. Although the aCPP model represents an important step forward as a pain assay, it does not distinguish between analgesic effects of a drug versus affective effects.