David M. Dirig

Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli

We have examined the stability and sources of variation within the nociceptive model of rat hind paw withdrawal from an under-glass radiant stimulus (Hargreaves et al., 1988) using a system where stimulus intensity and floor temperature can be controlled and reproducibly changed. The current study demonstrates that: (i) increased stimulus intensity with a fixed surface temperature is associated with a monotonic decrease in mean response latency and its variance; (ii) for a fixed stimulus intensity, the mean paw withdrawal latency and variance increased as the glass floor temperature is lowered from 30 degrees C to room temperature (25 degrees C). Using subcutaneously-implanted thermocouples and a 30 degrees C glass surface, the subcutaneous paw temperature observed at an interval corresponding to the time at which the animal displayed a paw withdrawal did not differ across multiple heating rates (41-42.5 degrees C). This finding is in agreement with human studies of pain thresholds and C-fiber activity. These studies emphasize the importance of maintaining a fixed surface temperature to reduce experimental variability and the utility of this apparatus across multiple stimulus intensities to define agonist efficacy.

Differential right shifts in the dose-response curve for intrathecal morphine and sufentanil as a function of stimulus intensity

&NA; To assess effects of stimulus intensity, dose‐response curves in rats for radiant heat‐evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu‐opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = 14.5 ± 0.3; medium = 8.9 ± 0.2; high = 5.7 ± 0.1 sec. After i.t. administration of sufentanil or morphine, there was a dose‐dependent, naloxone‐reversible elevation in nociceptive threshold. With increased stimulus intensity, there was a right shift in the dose‐response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED50 Medium/ED50 Low and ED50 High/ED50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2–2.9) and 7.7 (6.7–8.9), and the dose ratio for morphine (ED50 Medium/ED50 Low) was 34 (28–41). At the highest intensity, due to a plateau in the morphine dose‐response curve, ED50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupany, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.

Effect of spinal cyclooxygenase inhibitors in rat using the formalin test and in vitro prostaglandin E2 release.

Spinally delivery of the non-specific cyclooxygenase inhibitor, S(+)-ibuprofen, reduces the second phase of the formalin test and the evoked release of prostaglandin E2 (prostaglandin E2) from rat spinal cord in vitro. Using two selective cyclooxygenase-2 inhibitors, SC58125 (1-[(4-methysufonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl)p yrazole) and SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide), we observed that neither agent at the highest dose/concentration employed altered the second phase of the formalin test after intrathecal delivery or K+-evoked prostaglandin E2 release from spinal cord in vitro, although ibuprofen was effective in both models. These observations suggest that cyclooxygenase-2 may not be associated with spinal prostanoid synthesis acutely or with facilitated nociception which occurs within the limited time frame of the formalin test.

Mechanism of Action of Nonsteroidal Anti-inflammatory Drugs

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) dates back to thousands of years when man used natural sources of these agents in a lot of pain and inflammatory conditions. The tone for modern day discovery and use of NSAIDs was set with the discovery of aspirin. Today in addition to aspirin, a host of other NSAIDs of varying potency and efficacy is employed in the management of pain and inflammatory conditions. This chapter looks with key interest in the existing and evolving role of NSAIDs in therapeutics with emphasis on the current insights into their mechanism of action and side effect profiles associated with its use in pain and inflammation as well as its potential therapeutic benefits in cancer chemotherapy.

In vitro prostanoid release from spinal cord following peripheral inflammation: effects of substance P, NMDA and capsaicin.

Spinal prostanoids are implicated in the development of thermal hyperalgesia after peripheral injury, but the specific prostanoid species that are involved are presently unknown. The current study used an in vitro spinal superfusion model to investigate the effect of substance P (SP), N‐methyl‐d‐aspartate (NMDA), and capsaicin on multiple prostanoid release from dorsal spinal cord of naive rats as well as rats that underwent peripheral injury and inflammation (knee joint kaolin/carrageenan). In naive rat spinal cords, PGE2 and 6‐keto‐PGF1α, but not TxB2, levels were increased after inclusion of SP, NMDA, or capsaicin in the perfusion medium. Basal PGE2 levels from spinal cords of animals that underwent 5–72 h of peripheral inflammation were elevated relative to age‐matched naive cohorts. The time course of this increase in basal PGE2 levels coincided with peripheral inflammation, as assessed by knee joint circumference. Basal 6‐keto‐PGF1α levels were not elevated after injury. From this inflammation‐evoked increase in basal PGE2 levels, SP and capsaicin significantly increased spinal PGE2 release in a dose‐dependent fashion. Capsaicin‐evoked increases were blocked dose‐dependently by inclusion of S(+) ibuprofen in the capsaicin‐containing perfusate. These data suggest a role for spinal PGE2 and NK‐1 receptor activation in the development of hyperalgesia after injury and demonstrate that this relationship is upregulated in response to peripheral tissue injury and inflammation.

Hyperalgesia-Associated Spinal Synthesis and Release of Prostaglandins

Following tissue injury, an animal will display spontaneous pain behavior and an exaggerated response to a noxious stimulus, a state otherwise referred to as hyperalgesia. Consistent with the behavioral effects, injury or inflammation produces a left shift in the relationship between discharge rates of primary afferents and stimulus intensity (Reeh et al., 1986). This peripheral hypersensitivity can be explained, in part, by a local release of pro-inflammatory substances, such bradykinin or prostaglandins (Baccaglini and Hogan, 1983). Vane (1971) and Smith and Willis (1971) revealed that agents such as acetylsalicylic acid and indomethacin, which were known to alter the hyperalgesia which occurred secondary to inflammation (e. g. tissue injury), inhibited cyclooxygenase (COX), the enzyme responsible for prostaglandin synthesis. This observation provided a unifying link in explaining the ability of a diverse class of agents called non-steroidal anti-inflammatory drugs (NSAIDs), to normalize the otherwise lowered thresholds (i. e. hyperalgesia) observed in the face of local tissue injury (Ferreira et al., 1971).