Suppression of Noxious Stimulus-Evoked Activity in the Ventral Posterolateral Nucleus of the Thalamus by a Cannabinoid Agonist: Correlation between Electrophysiological and Antinociceptive Effects

Abstract

The CNS contains a putative cannabinergic neurotransmitter and an abundance of G-protein-coupled cannabinoid receptors. However, little is known about the function of this novel neurochemical system. Cannabinold agonists produce antinociception in behavioral tests, suggesting the possibility that this system serves in part to modulate pain sensitivity. To explore this possibility, the effects of the cannabinoid agonist WIN 55,212-2 on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus were examined in urethane-anesthetized rats. After identification of a nociresponsive neuron, a computer-controlled device delivered graded pressure stimuli to the contralateral hindpaw. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, i.v.) suppressed noxious stimulus-evoked activity of VPL neurons in a dose-dependent and reversible manner. Noxious stimulus-evoked firing was affected more than spontaneous firing. These effects were apparently mediated by cannabinoid receptors, because the cannabinoid receptor-inactive enantiomer of the drug (WIN 55,212-3, 0.25 mg/kg) failed to alter the activity of this population of cells. Administration of morphine (0.5 mg/kg, i.v.) produced effects that were very similar to those produced by the cannabinoid. WIN 55,212-2 (0.25 mg/kg, i.v.) failed to alter the responses of non-nociceptive low-threshold mechanosensitive neurons in the VPL WIN 55,212-2 produced antinociceptive effects with a potency and time course similar to that observed in the electrophysiological experiments, despite the differences in the anesthetic states of the animals used in these experiments. The antinociceptive and electrophysiological effects on VPL neurons outlasted the motor effects of the drug. Furthermore, the changes in nociceptive responding could not be attributed to changes in skin temperature. Taken together, these findings suggest that cannabinoids decrease nociceptive neurotransmission at the level of the thalamus and that one function of endogenous cannabinoids may be to modulate pain sensitivity.

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

“…*P Ͻ 0.05 vs. Vehicle/Vehicle and MethAnand/Cap. Martin et al, 1995;Lichtman et al, 1996;Martin et al, 1996;Hohmann and Herkenham, 1997;Richardson et al, 1998a,b). Thus, one possible interpretation of the ability of i.pl.…”

“…Additionally, in the last few decades selective synthetic cannabinoids have been developed and endogenous cannabinoids discovered (Lemberger and Rowe, 1975;Johnson et al, 1981;D'Ambra et al, 1992;Devane et al, 1992;Hanus et al, 1993;Mechoulam et al, 1995;Sugiura et al, 1995). Such developments have resulted in the determination that activation of central cannabinoid receptors produces antinociception (Yaksh, 1981;Herkenham et al, 1991;Lichtman and Martin, 1991;Martin et al, 1993Martin et al, , 1995Martin et al, , 1996Smith et al, 1994;Hohmann et al, 1995;Lichtman et al, 1996;Hohmann and Herkenham, 1997;Richardson et al, 1998a,b).…”

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia

“…immobility, catalepsy) that may confound interpretation of behavioral studies of antinociception that largely measure motor responses to noxious stimulation (Martin et al, 1991). Electrophysiological studies demonstrate that analgesic effects of exogenous cannabinoids are independent of motor deficits induced by these compounds (Martin et al 1996;Meng et al 1998). Nonetheless, due to the potential for such confounds, it is necessary to demonstrate that apparent antinociceptive effects observed in behavioral studies are not experimental artifacts attributable to motor suppression.…”

Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes

“…They are present in brain areas involved in nociceptive perception, such as the thalamus and amygdala (Fig. 1B) [93,99]. CB 1 receptors are also expressed in cells of the midbrain periaqueductal grey matter (PAG), and in the substantia gelatinosa of the spinal cord (receiving nociceptive input from primary afferent neurons), which are key sites for modulating nociceptive information [87,92,106].…”