Lawrence Melvin and Ross Johnson derived the experimental cannabinoid isomer, CP-55,940, that was essential to the discovery of the cannabinoid receptor system. In 1993 they joined with Martin, Razdan, Compton and Kenner Rice and Brian De Costa to correlate the receptor binding with in Vivo activities and establish a Structure-Activity Relationship between the two. (43)

"The results presented in this manuscript clearly indicate that behavioral potency of cannabinoids in the mouse can be predicted by establishing the affinity of the cannabinoid receptor labeled by [3H] CP-55,940."(44)

The high correlation between binding and in vivo pharmacological effects:

"suggest a lack of species differences in terms of receptor SAR, despite the fact that the pharmacological effects measured between each species do not necessarily appear to be related to one another. Additionally, these correlations were established using a set of cannabinoids incorporating a wide degree of structural diversity, and this set includes natural cannabinoids, cannabinoid metabolites, dimethylheptyl (or related) side chain analogs, nonclassical bicyclic cannabinoids, halegenated analogs and other synthetic analogs including stereoisomers. Thus, in the process of establishing these correlations, data presented here further enhance the body of knowledge concerning the structural requirements for binding to the cannabinoid receptor. . . Lastly, data presented here suggests that a single cannabinoid receptor exists to which almost all cannabinoids bind as a single recognition site. However some cannabinoids such as CBD may produce pharmacological actions either by interacting at this receptor at a different recognition site, or by another receptor mechanism altogether. No evidence is presented here which would suggest which is likely to occur."(45)

Melvin and Johnson also published a study that elucidated the SAR's of bicyclic cannabinoid analogs in light of the receptor breakthrough. (46)

A 1994 study indicated that D9-THC and kappa opiod agonists may share a common mechanism of action in the production of antinociception. (47) Opiods affect three distinct receptors, mu, delta, and kappa. Antagonists shut down receptor systems, closing the receptors to agonist or ligand binding. While mu-selective and delta-selective antagonists had no affect on the pain-killing effects of D9-THC, a kappa-selective antagonist also blocked the antinociception effects of D9-THC. This is the first evidence that cannabinoid antinociception has a different mechanism of action than the other behavioral effects of cannabinoids. This suggests that cannabinoids provide a means to activate pain-killing capabilities in the body previously accessible only through the use of opiod agonists or opiod drugs such as heroin and morphine, but without the significant safety risks that accompany opiod use. (Unlike opiods, cannabinoids to not depress the respiratory or pulmonary systems.)

Also in 1994, Herkenham's finding that down-regulation of cannabinoid receptors was responsible for tolerance to THC was replicated by a research team in Spain led by F. Rodriguez De Fonseca. (48)

However Dr. Herkenham's valuable discoveries did not end with the characterization of tolerance.