Richard L. Cannon

Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome

&NA; Although individuals with fibromyalgia syndrome (FMS) consistently report wide‐spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind‐up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind‐up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2–5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after‐sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.

Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients

&NA; We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat‐induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre‐drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A‐delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap‐induced windup when compared with age‐ and sex‐matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A‐delta‐nociceptive afferent input. Heat and cold‐induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 &mgr;g/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations.

The effect of time following exposure to trimethyltin (TMT) on cholinergic muscarinic receptor binding in rat hippocampus

Adult male Long-Evans rats were given 6 mg/kg trimethyltin (TMT). Rats were killed 1, 3, 7, 14, 21, 35, or 60 d later. An untreated control group was included. Brain sections were processed using film autoradiography to visualize in the hippocampus either total muscarinic receptor binding ([3H]quinuclidinyl benzilate; [3H]QNB), or M1 receptors ([3H]pirenzepine; [3H]PZ), or M2 receptors ([3H]oxotremorine-M; [3H]OXO-M). A reduction in [3H]QNB binding was found in CA1 and CA3c 7 d after TMT, but not in CA3a, b, or the dentate gyrus. [3H]PZ binding was decreased throughout Ammons horn by 14 d after treatment. [3H]OXO-M binding decreased 1 d after exposure in CA1 and in all subfields of Ammons horn by d 3. Neither [3H]PZ or [3H]OXO-M binding decreased in the dentate gyrus of TMT-treated rat at any time point. The temporal patterns of receptor loss may be explicable by reference to timing of fiber and cell body degeneration reported in previous studies and the regional differences may account for discrepancies between reports of either substantial decreases or no loss in hippocampal muscarinic receptors after TMT exposure.

A preclinical model of hyperalgesia following spinal stenosis/compression

Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long‐term evaluation of individual subjects because of the variability in effect over time for humans.

Effects of trimethyltin (TMT) on choline acetyltransferase activity in the rat hippocampus. Influence of dose and time following exposure.

Trimethyltin (TMT) destroys specific subfields of the hippocampus in the rat. TMT also increases choline acetyltransferase (ChAT) activity in CA1 of Ammons horn and the outer molecular layer of the dentate gyrus. This observation suggests that axonal sprouting occurs in the cholinergic septohippocampal system in response to TMT. However, neither does-response nor time course data are available for the effects of TMT on this enzyme. The effects of three dose levels of TMT on ChAT activity in CA1 and the dentate gyrus were determined in Experiment 1 and ChAT activity in these two areas was measured at six time points following exposure to TMT in Experiment 2. Only the highest dose of TMT (6 mg/kg) significantly increased ChAT activity. ChAT activity in the dentate gyrus increased significantly by 3 d after administration and continued to increase until 21 d after exposure. A significant increase was not observed in CA1 until 7 d after exposure to TMT. Asymptotic levels were still reached at d 21. These results indicate a steep dose-response curve for TMT-induced changes in ChAT activity in the hippocampal formation and that this marker of cholinergic activity is more sensitive to perturbation by TMT in the dentate gyrus than Ammons horn.

Sex differences in effects of excitotoxic spinal injury on below-level pain sensitivity.

Effects of excitotoxic injury to the thoracic gray matter on sensitivity to below-level nociceptive stimulation were evaluated for female and male Long-Evans rats. Operant escape and lick/guard (L/G) reflex responses to thermal stimulation were evaluated before and for 13-15 weeks after: 1) injections of quisqualic acid (QUIS) into the thoracic gray matter (T8-9), 2) laminectomy and spinal exposure and penetration without injection (sham) or 3) no surgical procedure (control). L/G responding to heat stimulation (44 °C) was unaffected for females and males following thoracic QUIS injections. Similarly, male escape performance was not significantly altered for 44 °C or 10 °C stimulation after QUIS injections or sham surgery. However, escape testing following QUIS and sham injections revealed increased heat sensitivity (44 °C) and decreased cold sensitivity (10 °C) for females. This selective effect is indicative of altered sympathetic activation by the thoracic injections. The effect of sham surgery suggests that female rats are vulnerable to ischemic injury during exposure and manipulation of the spinal cord. Escape from nociceptive heat and cold sensitivity of control males and females was unchanged over 13-15 weeks of testing.