Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.

A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague-Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of DRG or spinal “neuropathic markers” following SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (i.e., OFF) and excitatory (i.e., ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in non-allodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α2 adrenergic receptors precipitated allodynia in previously non-allodynic HZ rats with SNL. All rats showed an equivalent first phase formalin responses. However, HZ rats had reduced second phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve-injury induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.

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Opioids can induce hyperalgesia in humans and in animals. Mechanisms of opiate-induced hyperalgesia and possibly of spinal antinociceptive tolerance may be linked to pronociceptive adaptations occurring at multiple levels of the nervous system including activation of descending facilitatory influences from the brainstem, spinal neuroplasticity, and changes in primary afferent fibers. Here, the role of NK-1 receptor-expressing cells in the spinal dorsal horn in morphineinduced hyperalgesia and spinal antinociceptive tolerance was assessed by ablating these cells with intrathecal injection of SP-saporin (SP-SAP). Ablation of NK-1 receptor expressing cells prevented (a) morphine-induced thermal and mechanical hypersensitivity, (b) increased touchevoked spinal FOS expression, (c) upregulation of spinal dynorphin content and (d) the rightward displacement of the spinal morphine antinociceptive dose-response curve (i.e., tolerance). Morphine-induced hyperalgesia and antinociceptive tolerance were also blocked by spinal administration of ondansetron, a serotonergic receptor antagonist. Thus, NK-1 receptor expressing neurons play a critical role in sustained morphine-induced neuroplastic changes which underlie spinal excitability reflected as thermal and tactile hypersensitivity to peripheral stimuli, and to reduced antinociceptive actions of spinal morphine (i.e., antinociceptive tolerance). Ablation of these cells likely eliminates the ascending limb of a spinal-bulbospinal loop that engages descending facilitation and elicits subsequent spinal neuroplasticity. The data may provide a basis for understanding mechanisms of prolonged pain which can occur in the absence of tissue injury.

The clinically important opioid fentanyl, administered acutely, enhances mechanical hypersensitivity in a model of surgical pain induced by plantar incision. Activity of neurokinin-1 (NK-1) receptor-expressing ascending spinal neurons, descending pathways originating in the rostral ventromedial medulla (RVM), and spinal dynorphin are necessary for the development and maintenance of hyperalgesia during sustained morphine exposure, suggesting that these mechanisms may also be important in opioid enhancement of surgical pain. Therefore, we examined the roles of these mechanisms in sensory hypersensitivity produced by acute fentanyl administration in rats not undergoing surgical incision and in rats undergoing plantar incision. In non-operated rats, fentanyl induced analgesia followed by immediate and long-lasting sensory hypersensitivity, as previously described. Fentanyl also enhanced pain sensitivity induced by plantar incision. Ablation of NK-1-expressing spinal neurons by pre-treatment with substance P-Saporin reduced sensory hypersensitivity in fentanyl-treated rats and, to a lesser extent, in fentanyl-treated rats with a surgical incision. Microinjection of lidocaine into the RVM completely reversed fentanyl-induced sensory hypersensitivity and fentanyl enhancement of incision-induced sensory hypersensitivity. RVM lidocaine injection resulted in a slight reduction of incision-induced sensory hypersensitivity in the absence of fentanyl pre-treatment. Spinal dynorphin content increased by 30 +/- 7% and 66 +/- 17% in fentanyl- and fentanyl/incision-treated rats. Spinal administration of antiserum to dynorphin attenuated sensory hypersensitivity in fentanyl-treated rats. These data support a partial role of NK-1 receptor-containing ascending pathways and a crucial role of descending facilitatory pathways in fentanyl-induced hyperalgesia and in the enhanced hyperalgesia produced by fentanyl treatment following surgical incision.

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