A diminution of Δ9-tetrahydrocannabinol modulation of dynorphin A-(1-17) in conjunction with tolerance development

Previous research in this laboratory concerning Delta(9)-tetrahydrocannabinol-induced spinal antinociception indicated the critical role of dynorphin A-(1-17) in spinal antinociception following acute intrathecal (i.t.) administration. In the present study, tolerance development to Delta(9)-tetrahydrocannabinol-induced spinal antinociception attenuated Delta(9)-tetrahydrocannabinol-induced modulation of immunoreactive dynorphin A-(1-17). These data indicate that at lower doses of drug, desensitization of the cannabinoid receptor inhibits stimulation of downstream dynorphinergic neurons. However, at higher doses of drug, desensitization is overcome and spinal dynorphin A concentrations are increased by Delta(9)-tetrahydrocannabinol Antinociception in the absence of elevated dynorphin A-(1-17) levels in the tolerant rat suggests that factors other than the attenuated dynorphin release are components of antinociception in the tolerant state. The shift from the critical role of dynorphin A in cannabinoid antinociception vs, that in the non-tolerant state may indicate tolerance also at the kappa-opioid receptor, a role as yet undetermined. (C) 1999 Elsevier Science B.V. All rights reserved.