Introduction
Cannabinoid receptors 1 (CB1R) and 2 (CB2R) are integral components of the endocannabinoid system and play key roles in modulating immune responses and tumor progression. The orphan receptor GPR55, sometimes referred to as a “third cannabinoid receptor,” has been increasingly implicated in oncogenesis, being associated with pro-proliferative and pro-metastatic signaling. Canine oral melanomas, particularly the amelanotic subtype, are highly aggressive and share biological similarities with human mucosal melanomas, making them valuable spontaneous models for translational research.

Aims
To assess the immunohistochemical expression of CB1R, CB2R, and GPR55 in canine amelanotic oral melanomas.

Methodology
Twenty samples of canine oral amelanotic melanomas were analyzed. Indirect immunohistochemistry was performed using anti-CB1R (Origen®), anti-CB2R (Abcam®), and anti-GPR55 (Abcam®) antibodies, diluted 1:100, 1:200, and 1:200, respectively. Mucosa epithelium served as internal positive controls. Receptor expression in neoplastic cells was semi-quantitatively scored on a scale from 0 (negative) to 3 (strong) by three independent blinded observers.

Results
CB1R expression was absent or minimal (<10% of tumor cells) in 62% of cases. CB2R exhibited moderate and diffuse expression (score 2) in all samples. GPR55 is positive in normal epidermis, which served as an internal positive control. All samples were positive to this marker. In most amelanotic neoplasms, moderate positivity (grade II) was observed, and in some cases the nuclear membrane is also positive, with the same intensity. Melanocytes with melanin, scattered throughout the dermis and epidermis, are intensely (grade III) marked. All controls were positive.

Conclusions
The minimal CB1R expression and the consistent presence of CB2R and GPR55 suggest preferential involvement of CB2R and GPR55 in the biology of amelanotic melanomas. While functional associations with proliferation or metastatic behavior cannot be established from these results alone, the observed expression patterns support the need for further studies addressing their role in tumor aggressiveness, immune modulation, and metastatic potential. These findings suggest CB2R and GPR55 as promising candidates for future investigation as biomarkers and therapeutic targets in melanoma comparative oncology.