ReviewComparison of operant escape and reflex tests of nociceptive sensitivity
Section snippets
Comparison of reflex and operant escape responses to nociceptive stimulation of normal monkeys, rats and humans
For stimuli of sufficient intensity to elicit reflexes, response latencies distinguish flexion/withdrawal reflexes from operant escape responses. In studies of Macaca speciosa monkeys and Long-Evans rats, electrical stimulation has been delivered to one hindlimb while simultaneously recording flexion/withdrawal of the stimulated limb and operant escape. Manual lever pulls (monkeys) or bar press responses (rats) with either hand terminate stimulation of the leg that responds with
CNS circuits in support of reflex and operant escape responding
Separate neural circuits participate in the generation of reflex and operant escape responses. Spinal neurons provide output to the periphery or the brain stem or the cerebrum for the 3 behavioral categories emphasized in this review.
Laboratory animal models of neuropathic pain following peripheral injury
Different methods of ligating or partially transecting a peripheral nerve have been utilized to provide animal models of neuropathic pain. In these models, flexion/withdrawal reflexes are enhanced (shorter latencies for thermal stimulation or lower thresholds for mechanical stimulation) for the treated hindlimb relative to the contralateral hindlimb when similarly stimulated. One of these models, chronic constriction injury (CCI) of the sciatic nerve, produces an ipsilateral enhancement of
Effects of spinal cord injury (SCI) on nociceptive reflexes and on pain sensitivity
Operant escape testing has consistently confirmed clinical evidence from humans (King, 1957, White and Sweet, 1969) that interruption of the lateral spinothalamic tract initially produces contralateral hypoalgesia, below the level of the lesion (Vierck et al., 1971, Vierck et al., 1983b, Vierck et al., 1986, Vierck et al., 1990, Vierck et al., 1995, Vierck et al., 2000, Vierck and Light, 1999, Vierck and Light, 2000, Vierck and Light, 2002, Vierck and Luck, 1979). In contrast to the
Stress-induced analgesia or hyperalgesia?
An extensive literature involving laboratory animal subjects and reflex measures has portrayed acute psychological stress as analgesic (Bodnar et al., 1980). Probably, stress-induced hypoalgesia is a real but time-limited effect, judging from anecdotal reports of performance feats during stress associated with painful injury. However, it is problematic to evaluate pain sensitivity during presentation of most stressors, because of distraction. Therefore, the standard experimental paradigm for
Sex differences in reflex and operant escape responding to thermal stimulation
Whether there are meaningful differences in pain sensitivity for males and females has received considerable attention in recent years. Human psychophysical studies have concluded that females are more sensitive to pain (Riley et al., 1998), and there is a higher prevalence of chronic pain conditions among females (Unruh, 1996). Interpretation of these studies is complicated by psychosocial influences that can predispose females to exaggerate pain more than males (Jackson et al., 2005, Kallai
Effect of age on escape and thermal preference testing
Escape testing of female Fischer 344 × Brown Norway rats (bred for longevity) has revealed hyperalgesia for 15 °C, 10 °C, 42 °C, and 44.5 °C stimulation of 32 month-old females, compared to 8 or 16 month-old females (Yezierski et al., 2010). Cold sensitivity increases with age to a greater extent than heat sensitivity. This has been confirmed by changing our escape task from an opposition of bright light vs. heat or cold to an opposition of heat vs. cold stimulation. Thermal preference testing of
Effects of systemic morphine on pain sensitivity of humans, monkeys and rats
Systemic μ-opioid agonists have long been considered the most powerful pharmacological agents for inhibition of pain. However, attempts to understand mechanisms of opioid hypoalgesia have been misdirected by the prevalent methods of antinoceptive testing of humans and laboratory animals. Primary considerations are that: (A) reflexes do not reveal opioid actions at sites throughout the neuraxis known to contain opioid receptors (Becerra et al., 2013, Hagelberg et al., 2012, Maarrawi et al., 2007
Loss of cholinergic basal forebrain neurons and systemic cholinergic antagonism
Cholinergic agonists are antinociceptive when administered intrathecally to humans (Bartolini et al., 2011, Jones and Dunlop, 2007), and nociceptive reflexes are attenuated following intrathecal application of cholinergic agonists (Bouaziz et al., 1995, Eisenach and Gebhart, 1995, Gillberg et al., 1990, Hartvig et al., 1989, Yaksh et al., 1985). Also, reflex responses are inhibited by systemic or intracerebral administration of cholinergic agonists or acetylcholinesterase antagonists (Abelson
Controls and other methodological considerations
It is obvious that controls are needed to insure that effects on behavioral reactions to stimulation represent a modulation of nociceptive sensitivity. More accurately, the importance of controls is understood for operant escape, but this has not been the case for reflex tests. For example, morphine is expected to inhibit pain selectively. However, doses of morphine too low to attenuate reflexes can reduce escape responding to non-nociceptive stimulation. Similar procedures could have
Semantics: pain modulation vs. motor control
Different categories of altered pain sensitivity, such as allodynia, hyperalgesia, hypoalgesia or analgesia have been defined relative to thresholds for consciously perceived pain intensity (IASP, 1994). Clearly, these definitions do not relate or refer to any characteristic of reflex responses to nociceptive stimulation. And yet, reports of laboratory animal experiments have consistently referred to effects of experimental manipulations on nociceptive reflexes as allodynia, hyperalgesia, or
Pain research strategies
Preclinical testing of pharmacological agents with a potential for pain modulation has almost exclusively utilized reflex tests. Much of this screening is conducted by pharmaceutical companies without publication of the drugs tested or the results. The strategy appears to be that reflexes provide an efficient means of screening the actions of multiple drugs in laboratory animals, and then promising agents can be evaluated with conscious reports by humans. This is a flawed approach on numerous
Summary and implications
The investigation of unmotivated, innate reflexes that primarily serve motor control from the brain stem is not relevant to pain. Study of a simple circuit from the periphery to spinal interneurons and then to motoneurons will not reveal functions of different and more extensive circuits from the periphery to the cerebral cortex. Activation of the cerebral targets of nociceptive projection is necessary for evocation of pain sensations and for motivated programming of escape responses (Bushnell
Conflict of interest
One of the authors (C.J.V.) is a board member of Neuroanalytics, a company that has developed automated equipment for human psychophysical testing and for operant and reflex testing of laboratory animals.
Acknowledgements
Research summarized in this review was supported by: NIH grant NS-07261, funds supplied by the University of Florida Department of Neuroscience and Brain Institute, NIA grant RAG-031821, and a grant for international collaboration from the International Association for the Study of Pain, Scan Design and the Bruun Foundation. The technical support of Jean Kaufman and Karen Murphy is gratefully acknowledged, for their assistance in the studies reported here, involving expert handling and care of
References (265)
Spinal transection increases the potency of clonidine on the tail-flick and hindlimb flexion reflexes
Eur. J. Pharmacol.
(2002)- et al.
Behavioural pain-related disorders and contribution of the saphenous nerve in crush and chronic constriction injury of the rat sciatic nerve
Pain
(1994) - et al.
Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: evaluation of pain-like behavior
Pain
(2010) - et al.
Pain characteristics in patients admitted to hospital with complications after spinal cord injury
Arch. Phys. Med. Rehabil.
(2003) - et al.
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Pain
(1988) - et al.
A physiologically based clinical measure for spastic reflexes in spinal cord injury
Arch. Phys. Med. Rehabil.
(2005) Progressive degradation of serial grooming chains by descending decerebration
Behav. Brain Res.
(1989)- et al.
Stress-induced analgesia: neural and hormonal determinants
Neurosci. Biobehav. Rev.
(1980) - et al.
Dose-dependent reductions by naloxone of analgesia induced by cold-water stress
Pharmacol. Biochem. Behav.
(1978) - et al.
Comparison of motor reflex and vocalization thresholds following systemically administered morphine, fentanyl, and diazepam in the rat: assessment of sensory and performance variables
Pharmacol. Biochem. Behav.
(1994)