Jennelle Durnett Richardson

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

&NA; 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 CB1 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 CB1 cannabinoid receptor subtype as indicated by its reversal with the CB1 receptor antagonist SR 141716A. Additionally, peripheral, but not systemic, administration of 0.01 ng anandamide inhibited edema. Peripherally administered cannabinoids also interacted with CB1 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 capsaicin‐evoked release of calcitonin gene‐related peptide from isolated hindpaw skin. Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB1 receptor. A potential mechanism for this effect is the inhibition of neurosecretion from capsaicin‐sensitive primary afferent fibers.

Antihyperalgesic effects of spinal cannabinoids

Cannabinoids have been widely reported to produce antinociception in models such as tail flick and hot plate. However, their role in modulating thermal hyperalgesia is unknown. The potency of some drugs, such as the opioids, increases during hyperalgesia. Thus, we evaluated whether there is a change in the effectiveness of intrathecal cannabinoids with hyperalgesia. Additionally, we evaluated whether cannabinoids could inhibit capsaicin-evoked neurosecretion from isolated rat spinal cord. Our results indicate that 1 fmol anandamide (i.t.) completely blocked carrageenan-induced thermal hyperalgesia. However, anandamide at doses as high as 100 pmol had no effect on thermal latencies in normal animals. Additionally, anandamide inhibited K+- as well as capsaicin-evoked immunoreactive calcitonin gene-related peptide release. Finally, cannabinoid receptors were identified in sensory neurons. Collectively, these results indicate that there is an increased effectiveness of modulation of thermal nociceptive thresholds by spinal cannabinoids during hyperalgesia. This antihyperalgesic effect may be the result of cannabinoid-induced inhibition of neurosecretion from certain primary afferent fibers.

Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats

While the effects of excitatory amino acids have been well characterized in the central nervous system, relatively little is known about their possible modulation of elements responsible for hyperalgesia within peripheral tissue. The presented experiments demonstrate that the intraplantar (i.pl.) injection of L-glutamate (30 nmol) evokes a thermal hyperalgesic response in the paw withdrawal latencies of normal rats which is stereospecific. In addition, the i.pl. injection of either the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (10 nmol) or the competitive alpha-amino-3-hydroxy-4-methyl-5-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)(100 nmol) into hindpaws inflamed with carrageenan significantly reduced the thermal hyperalgesic response in rats. Collectively, these results suggest that excitatory amino acids activate a peripheral target which facilitates a hyperalgesic behavioural response to thermal stimulation via a receptor mediated process.

SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice

Antinociceptive effects of cannabinoids are well documented. However, the physiological role of endogenous cannabinoids in nociception is unknown. We evaluated the effects of the cannabinoid receptor antagonist SR 141716A (N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide) on mouse hot plate latencies. Intrathecal injection of SR 141716A evoked a significant thermal hyperalgesia. These results suggest that the cannabinoid system tonically regulates thermal nociceptive thresholds. Furthermore, the absence of this regulation results in hyperalgesia suggesting that hypoactivity of this system may be involved in certain types of chronic pain.

Cannabinoids modulate pain by multiple mechanisms of action

Abstract Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects.

Evaluation of functional GABAB receptors in dental pulp

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that is elevated in inflamed human dental pulp. Because GABA agonists are antihyperalgesic in other tissue, it is possible that GABA agonists have similar effects in dental pulp assuming that this tissue contains GABA receptors. We tested the hypothesis that dental pulp contains functional GABA(B) receptors using a GTPgamma35S binding assay. This is a functional assay because GTPgamma35S will be bound to cell membranes only when activation of metabotropic receptors has lead to binding and activation of their associated G(alpha)-proteins via release of GDP and binding of the GTPgamma35S. Baclofen, a GABA(B) agonist, evoked GTPgamma35S binding in both human and bovine dental pulp. This was mediated by the GABA(B) receptor because it was blocked by the selective antagonist phaclofen in both tissues. The presence of GABA and its receptor, GABA(B), suggests that this system may be relevant in the production or management of endodontic pain.