Behavioral and neurochemical analysis of ongoing bone cancer pain in rats

Abstract

Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized following intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens shell (NAc) was observed following peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared to sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) mu opioid receptors (MOR). rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats, but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine, but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential

“…Our laboratory has evaluated pain motivated behavior and demonstrated that relief of ongoing pain is a natural reward that evokes DA release within the NAc [22; 59], consistent with human imaging studies [6; 7; 24; 62; 93]. We proposed that release of dopamine in the NAc by intrinsically non-rewarding treatments in the setting of injury could represent a translational biomarker of pain relief [24; 62; 69; 93]. In the present study, our data show that R9-CBD3-A6K reverses evoked hypersensitivity in nerve-injured rats.…”

“…We previously demonstrated that pairing a context with a treatment that effectively relieves ongoing pain produces preference for that context (i.e., conditioned place preference) through negative reinforcement. Removal of aversive states induced by ongoing pain by intrinsically non-rewarding treatments (e.g., peripheral nerve block with lidocaine or intravenous ketorolac [62; 69; 93]) are accompanied by release of dopamine in the nucleus accumbens (NAc) shell representing the natural reward of pain relief. Thus, assessment of NAc dopamine release was proposed as an objective, neurochemical translational biomarker of pain relief [24; 62; 69; 93]; this concept has been validated in post-surgical [61], cephalic [24], osteoarthritic [64], neuropathic [93], and cancer-induced bone [69] pain.…”

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain

“…CPP is dependent on the reward system. The enhanced dopamine (DA) released in the nucleus accumbens (NAc) shell was related to CPP in rats with tumor 27 or spinal nerve ligation (SNL). 28 Pharmacologic activation of the rACC opioid receptors of injured animals was sufficient to stimulate dopamine release in the NAc and produce CPP.…”

Brain Circuits Encoding Reward from Pain Relief

“…Associative relief learning is revealed by motivation to seek that context in the future. We and others have demonstrated CPP with pain relieving treatments in multiple experimental pain models including: neuropathic (SNL, spinal nerve injury; SNI, partial or complete axotomy, spinal cord lesions, cisplatin-induced polyneuropathy) (62-65), inflammatory (Complete Freund's Adjuvant, CFA) (66, 67), post-surgical (incisional) (68), bone cancer (69) and osteoarthritic (mono-iodoacetate, MIA) (70, 71) pain. Importantly, treatments that are not intrinsically rewarding but alleviate pain in humans (e.g., lidocaine-induced peripheral nerve blockade or intrathecal administration of ω-conotoxin (ziconotide) (72) or clonidine (73, 74) do not produce CPP in uninjured animals but can do so in the presence of ongoing pain.…”