Central antinociceptive effects of cannabinoids have been well documented. However, relatively little is known about the peripheral effects of the cannabinoids on inflammation. In the present study, we evaluated the effects of peripherally administered cannabinoids on three indices of inflammation: carrageenan-induced thermal hyperalgesia, carrageenan-induced edema, and capsaicin-induced plasma extravasation. In addition, we determined the effect of cannabinoids on capsaicin-evoked neuropeptide release from isolated rat hindpaw skin. Our results indicate that cannabinoids produce antihyperalgesia via interaction with a peripheral CB 1 receptor. Peripheral, but not systemic, administration of 0.01 ng anandamide inhibited the induction of hyperalgesia. Peripheral administration of anandamide also attenuated hyperalgesia after its development via interaction with the CB 1 cannabinoid receptor subtype as indicated by its reversal with the CB 1 receptor antagonist SR 141716A. Additionally, peripheral, but not systemic, administration of 0.01 ng anandamide inhibited edema. Peripherally administered cannabinoids also interacted with CB 1 receptors to inhibit capsaicin-evoked plasma extravasation into the hindpaw. One potential mechanism for the anti-inflammatory actions of the cannabinoids is the inhibition of neurosecretion from the peripheral terminals of nociceptive primary afferent fibers. This hypothesis is supported by the finding that anandamide inhibited capsaicinevoked release of calcitonin gene-related peptide from isolated hindpaw skin. Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB 1 receptor. A potential mechanism for this effect is the inhibition of neurosecretion from capsaicin-sensitive primary afferent fibers.

Since the initial observations that stimulation of sensory neurons produces vasodilation, plasma extravasation, and hypersensitivity, much progress has been made in understanding the etiology of neurogenic inflammation. Studies have focused largely on the role of the neuropeptides, substance P and calcitonin gene-related peptide, which are released in the periphery by activation of small diameter sensory neurons. Recent work, however, has begun to emphasize the cellular mechanisms involved in regulating the release of proinflammatory substances from sensory neurons. In this perspective, discussion centers on a number of inflammatory mediators that activate various signal transduction pathways to augment excitability of and transmitter release from sensory neurons. Emphasis is placed on those pathways where multiple lines of evidence support their importance in initiating neurogenic inflammation. Recent studies, however, support the notion that there are novel compounds released during injury that can stimulate or sensitize sensory neurons. Furthermore, only now are intracellular signaling pathways that have been identified in other cell systems being studied in sensory neurons to establish their role in neurogenic inflammation. The challenge remains to ascertain the critical transduction pathways that regulate transmitter release from sensory neurons since this phenomenon triggers neurogenic inflammation. In addition, the cellular mechanisms involved in alterations in neuronal excitability during injury and the cellular pathways that maintain the inflammatory response over time need to be determined. With these advances, we will be able to develop therapeutic interventions to minimize deleterious consequences of neurogenic inflammation. Neurogenic InflammationMore than a century ago, the first observations were made that activation of dorsal root ganglia neurons results in vasodilation, suggesting that these neurons not only conduct afferent information to the spinal cord, but also subserve an efferent function (Bayliss, 1901). Since that time, abundant evidence has accumulated supporting the notion that activation of peripheral terminals of sensory neurons by local depolarization, axonal reflexes, or dorsal root reflexes releases bioactive substances. These substances, in turn, act on target cells in the periphery such as mast cells, immune cells, and vascular smooth muscle producing inflammation, which is characterized by redness and warmth (secondary to vasodilation), swelling (secondary to plasma extravasation), and hypersensitivity (secondary to alterations in the excitability of certain sensory neurons). We call this phenomenon "neurogenic inflammation", that is, inflammatory symptoms that result from the release of substances from primary sensory nerve terminals.Of major importance in the generation of neurogenic inflammation are the small diameter sensory neurons that are sensitive to capsaicin, the vanilloid found in hot peppers (for review, see Holzer, 1988). Intradermal injection of capsaicin ...

No abstract

Cannabinoids, such as Delta9-THC, are capable of inhibiting nociception, i.e., pain transmission, at least in part, by interacting with spinal Gi/Go-coupled cannabinoid receptors. What is not known, however, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then alterations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation of basal thermal nociceptive thresholds by the spinal cannabinoid system. Administration of oligonucleotides directed against CB1 cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer oligonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cannabinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hyperalgesia with an ED50 of 0.0012 fmol. The SR 141716A-induced hyperalgesia was dose-dependently blocked by the administration of D-AP-5 or MK-801, two antagonists to the NMDA receptor. These results indicate that there is tonic activation of the spinal cannabinoid system under normal conditions. Furthermore, hypoactivity of the spinal cannabinoid system results in an NMDA-dependent hyperalgesia and thus may participate in the etiology of certain chronic pain states.

No abstract