The perception of fatigue is common in many disease states, however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate, and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine if this combination could activate sensations, and if so determined how these subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30-s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis (APB). Infusion of individual metabolites at maximum amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4+300nM ATP+1mM lactate) also evoked no sensation. The infusion of a metabolite-combination found in muscle during moderate endurance-exercise (pH 7.3+400nM ATP+5 mM lactate) produced significant fatigue sensations. Infusion of a metabolite-combination associated with vigorous exercise (pH 7.2+500nM ATP+10mM lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischemic exercise) caused more ache but no additional fatigue-sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate, and ATP leads to fatigue-sensation and eventually pain, probably through activation of ASIC, P2X, and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

Repeated exposure to drugs of abuse produces forms of experience-dependent plasticity including behavioral sensitization. Although a single exposure to many addicting substances elicits locomotor sensitization, there is little information regarding the motivational effects of such single exposures. This study demonstrates that a single cocaine exposure enhances both rewarding and aversive forms of opioid place conditioning. Rats were given a single injection of cocaine (15 mg͞kg i.p.) in their home cage at different times before conditioning. This treatment enhanced conditioned place preference (CPP) to morphine (2 ؋ 10 mg͞kg s.c.) if training began 1 or 5 but not 10 days after the cocaine injection. A single cocaine exposure also enhanced conditioned place aversion (CPA) to the -opioid receptor agonist U69593 (2 ؋ 0.16 mg͞kg s.c.). Compared to morphine CPP, U69593 CPA was delayed and persistent. It was not observed at 1 day but appeared if the conditioning began 5 or 10 days after the cocaine injection. Although the cocaine-induced enhancements of both morphine CPP and U69593 CPA followed different time courses, suggesting different mechanisms, both effects were blocked by injection of the N-methyl-Daspartate receptor antagonist MK-801 (0.5 nmol bilaterally) into the ventral tegmental area, immediately before the cocaine injection. Thus, through a circuit involving the ventral tegmental area, a single cocaine exposure enhanced both -opioid receptor reward and -opioid receptor aversion.C hronic exposure to drugs of abuse produces enduring changes in neural circuits that underlie the addictive process. One consequence of this experience-dependent plasticity is a progressive increase in drug response on reexposure to the drug. Termed drug sensitization, the phenomenon is typically assessed as an enhancement in locomotor activity. Robust locomotor sensitization can be produced by psychostimulants (1), opiates (2), or ethanol (3), and cross-sensitization can occur between different drugs (4, 5).Whereas early studies of sensitization focused specifically on the progressive increase in locomotor activity (1), many researchers have since proposed that sensitization contributes to drug reward, and this process has been incorporated into several influential theoretical models of drug addiction. For example, sensitization processes have been proposed to contribute to impulsivity (6) or changes in incentive-salience state for cues associated with the drug (7). These proposals are supported by the observation that drug self-administration is enhanced after repeated drug administrations. For example, monkeys previously exposed to methamphetamine initiated self-administration to the stimulant at lower doses than drug-naïve subjects (8). Moreover, preexposure to amphetamine was sufficient to turn initial nonresponders into reliable self-administering rats (9). Finally, rats previously exposed to amphetamine exhibited higher break points than untreated rats to obtain the drug on a progressive ratio schedule of reinforcement (10...

Pain medicine claims have increased over time and have increased in severity. Claims related to cervical procedures were out of proportion to the frequency with which they are performed. These liability findings suggest that pain specialists should aggressively continue the search for safer and more effective therapies.

Background Due to an increase in implantable device–related anesthesia pain medicine claims, the authors investigated anesthesia liability associated with these devices. Methods After institutional review board approval, the authors identified 148 pain medicine device claims from 1990 or later in the Anesthesia Closed Claims Project Database. Device-related damaging events included medication administration events, infections, hematomas, retained catheter fragments, cerebrospinal fluid leaks, cord or cauda equina trauma, device placed at wrong level, stimulator incorrectly programmed, delay in recognition of granuloma formation, and other issues. Results The most common devices were implantable drug delivery systems (IDDS; 64%) and spinal cord stimulators (29%). Device-related care consisted of surgical device procedures (n = 107) and IDDS maintenance (n = 41). Severity of injury was greater in IDDS maintenance claims (56% death or severe permanent injury) than in surgical device procedures (26%, P < 0.001). Death and brain damage in IDDS maintenance claims resulted from medication administration errors (n = 13; 32%); spinal cord injury resulted from delayed recognition of granuloma formation (n = 9; 22%). The most common damaging events for surgical device procedures were infections, inadequate pain relief, cord trauma, retained catheter fragments, and subcutaneous hygroma. Care was more commonly assessed as less than appropriate (78%) and payments more common (63%) in IDDS maintenance than in surgical device procedure claims (P < 0.001). Conclusions Half of IDDS maintenance claims were associated with death or permanent severe injury, most commonly from medication errors or failure to recognize progressive neurologic deterioration. Practitioners implanting or managing devices for chronic pain should exercise caution in these areas to minimize patient harm.